Usp1 inhibitor

Abstract

The present application provides a class of novel compounds having USP1 inhibitory activity as shown in formula (II'), pharmaceutical compositions comprising the compounds, useful intermediates for preparing the compounds, and a method for treating related diseases mediated by a USP1 target by means of the compounds of the present application.

Description

[0001] The present application claims the benefits of the priority of the Chinese patent application filed before CNIPA on September 02, 2022, with the application No. CN202211069731.2 and titled "USP1 INHIBITOR"; the Chinese patent application filed before CNIPA on October 18, 2022, with the application No. CN202211272140.5 and titled "USP1 INHIBITOR"; the Chinese patent application filed before CNIPA on January 18, 2023, with the application No. CN202310084635.3 and titled "USP1 INHIBITOR"; the Chinese patent application filed before CNIPA on April 18, 2023, with the application No. CN202310416682.3 and titled "USP1 INHIBITOR"; the Chinese patent application filed before CNIPA on June 25, 2023, with the application No. CN202310755391.7 and titled "USP1 INHIBITOR"; and the Chinese patent application filed before CNIPA on August 25, 2023, with the application No. CN202311082622.9 and titled "USP1 INHIBITOR"; which are hereby incorporated in their entirety by reference.FIELD OF THE INVENTION

[0002] The present application relates to the field of medicinal chemistry, and involves a novel compound having USP1 inhibitory activity, a pharmaceutical composition comprising the compound, a useful intermediate for preparing the compound, and a method for treating related diseases mediated by a USP1 target by using the compound of the present application.BACKGROUND OF THE INVENTION

[0003] Ubiquitin is a small, highly conserved protein consisting of 76 amino acids, which attaches to a substrate protein (including itself) in a three-step enzymatic reaction. Initial covalent attachment occurs primarily between a C-terminal glycine of ubiquitin and a ε-amino group of a lysine residue of a target protein. Additional ubiquitin molecules can be attached to one of the seven internal lysines of ubiquitin, leading to different ubiquitin chain topologies. Biological outcome of ubiquitination is determined by length and connection topology. Similar to other types of post-translational modifications, ubiquitination is a reversible process that is counter-regulated by enzymes called deubiquitinating enzymes (DUBs), which catalyze the removal of ubiquitin from modified proteins. More importantly, dysfunction of ubiquitin-dependent signaling pathway is associated with a variety of human diseases, suggesting that inhibition of ubiquitin pathway is a novel therapeutic target for drug development.

[0004] The ubiquitin-proteasome system offers additional opportunities for therapeutic interventions, which may increase specificity and the potential for improved clinical efficacy. Most obvious targets include enzymes involved in ubiquitin conjugation and de-conjugation (i.e. ubiquitin ligases and DUBs), which are upstream processes of proteasome-mediated protein degradation. Among various DUBs, ubiquitin-specific protease 1 (USP1) is an attractive anticancer target due to its involvement in the regulation of DNA damage response pathway. USP1 binds to USP1-associated factor 1 (UAF1) to produce a heterodimeric USP1 / UAF1 complex required for the activity of deubiquitinating enzymes. The USP1 / UAF1 complex has been shown to modulate tolerance to DNA damage induced by a DNA cross-linking agent through deubiquitination of proliferating cell nuclear antigen (PCNA) 11 and Fanconi anemia complementation group D2 (FANCD2), which are proteins involved in translesion synthesis and the Fanconi anemia pathway, respectively.

[0005] There are currently many studies focusing on this mechanism, but there is no USP1 inhibitor on the market and there is an urgent need to develop an effective USP1 inhibitor for clinical patients.SUMMARY OF THE INVENTION

[0006] In a first aspect, the present application provides a compound represented by formula (II'), or an isomer thereof or a pharmaceutically acceptable salt thereof, wherein, X a is C or N; ring A is phenyl, 5-6 membered heteroaryl, C 5-6 cycloalkyl, or 5-6 membered heterocyclyl; R a are each independently deuterium, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, oxo, cyano, amino, hydroxy, aminosulfonyl, C 1-4 alkylsulfonyl, carbamoyl, C 1-4 alkylamino, C 3-6 cycloalkyl, C 1-4 alkylsulfonylamino, dimethylphosphonoyl, -C 1-4 alkyl-OH, -COOC 1-4 alkyl, C 1-4 alkyl-SO 2 -NR f -, HO-C 1-4 alkyl-SO 2 -NR f -, 3-6 membered heterocyclyl, -C 1-4 haloalkyl-OH, (C 1-4 alkyl) 2 P(O)-, deuterated C 1-4 alkyl, or 4-6 membered heterocycloalkyl; wherein C atom(s) in the C 1-4 alkyl and C 1-4 haloalkyl is / are optionally substituted with N or O; R f is C 3-6 cycloalkyl or C 1-4 alkyl; m is 0, 1, 2, 3, or 4; R b is H or C 1-4 alkyl; ring B is phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; R c are each independently halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or deuterated C 1-4 alkyl; n is 0, 1, 2, 3, or 4; ring D is phenyl, 5-6 membered heteroaryl, or 9-18 membered fused-heterocyclyl; R e is deuterium, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, ring C, or halogen, wherein ring C is optionally substituted with one R d ; ring C is 5-10 membered heteroaryl comprising 1 to 4 N atom(s) or 8-10 membered fused-heterocyclyl comprising 1 to 4 N atom(s); R d are each independently C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, or C 3-6 cycloalkyl; 1 is 1, 2, 3, or 4; p is 1, 2, 3, or 4; L 1 is C 1-4 alkylene, C 3-6 cycloalkylene or a chemical bond; when ring A is 5-6 membered heteroaryl, structural unit is not and when ring A is 5-6 membered heterocyclyl, structural unit is not

[0007] In some embodiments of the present application, in the compound represented by formula (II'), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring D is

[0008] In some embodiments of the present application, in the compound represented by formula (II'), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring D is

[0009] In some embodiments of the present application, in the compound represented by formula (II'), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring D is

[0010] In some embodiments of the present application, in the compound represented by formula (II'), or the isomer thereof or the pharmaceutically acceptable salt thereof, R e is -CF 3 , or

[0011] In some embodiments of the present application, in the compound represented by formula (II'), or the isomer thereof or the pharmaceutically acceptable salt thereof, R e is -OCH 3 , -F, -D, or -CH 3 .

[0012] In some embodiments of the present application, in the compound represented by formula (II'), or the isomer thereof or the pharmaceutically acceptable salt thereof, R e is -CF 3 .

[0013] The present application further provides a compound represented by formula (I'), or an isomer thereof or a pharmaceutically acceptable salt thereof: wherein, X a is C or N; X b , X c , and X d are each independently CH, N, or CR', wherein R' is halogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy; ring A is phenyl, 5-6 membered heteroaryl, C 5-6 cycloalkyl, or 5-6 membered heterocyclyl; R a are each independently deuterium, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, oxo, cyano, amino, hydroxy, aminosulfonyl, C 1-4 alkylsulfonyl, carbamoyl, C 1-4 alkylamino, C 3-6 cycloalkyl, C 1-4 alkylsulfonylamino, dimethylphosphonoyl, -C 1-4 alkyl-OH, -COOC 1-4 alkyl, C 1-4 alkyl-SO 2 -NR f -, HO-C 1-4 alkyl-SO 2 -NR f -, 3-6 membered heterocyclyl, -C 1-4 haloalkyl-OH, (C 1-4 alkyl) 2 P(O)-, wherein C atom(s) in the C 1-4 alkyl and C 1-4 haloalkyl is / are optionally substituted with N or O; R f is C 3-6 cycloalkyl or C 1-4 alkyl; m is 0, 1, 2, 3, or 4; R b is H or C 1-4 alkyl; ring B is phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; R c are each independently halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 1-4 haloalkyl, or C 1-4 haloalkoxy; n is 0, 1, 2, 3, or 4; ring C is 5-10 membered heteroaryl comprising 1 to 4 N atom(s); R d are each independently C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or deuterated C 1-4 alkyl; 1 is 0, 1, 2, 3, or 4; and L 1 is C 1-4 alkylene, C 3-6 cycloalkylene or a chemical bond.

[0014] When ring A is 5-6 membered heteroaryl, structural unit is not and when ring A is 5-6 membered heterocyclyl, structural unit is not

[0015] The present application further provides a compound represented by formula (I'-1), or an isomer thereof or a pharmaceutically acceptable salt thereof, wherein, X b , X c , and X d are each independently CH, N, or CR', wherein R' is halogen or C 1-4 alkoxy; ring A is phenyl, pyridinyl, or C 5-6 cycloalkyl; R a are each independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, oxo, cyano, amino, hydroxy, aminosulfonyl, C 1-4 alkylsulfonyl, carbamoyl, C 1-4 alkylamino, C 3-6 cycloalkyl, C 1-4 alkylsulfonylamino, dimethylphosphonoyl, -C 1-4 alkyl-OH, -COOC 1-4 alkyl, C 1-4 alkyl-SO 2 -NR f -, HO-C 1-4 alkyl-SO 2 -NR f -, 3-6 membered heterocyclyl, -C 1-4 haloalkyl-OH, (C 1-4 alkyl) 2 P(O)-, wherein C atom(s) in the C 1-4 alkyl and C 1-4 haloalkyl is / are optionally substituted with N or O; R f is C 3-6 cycloalkyl or C 1-4 alkyl; m is 0, 1, 2, 3, or 4; R b is H or C 1-4 alkyl; ring B is 5-6 membered heteroaryl or 5-10 membered heterocyclyl; R c are each independently C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or halogen; n is 0, 1, 2, 3, or 4; ring C is 5-6 membered heteroaryl comprising 1 to 4 N atom(s); R d are each independently C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy; 1 is 0, 1, 2, 3, or 4; and L 1 is C 1-4 alkylene or C 3-6 cycloalkylene.

[0016] In some embodiments of the present application, provided is a compound represented by formula (I'-1), or an isomer thereof or a pharmaceutically acceptable salt thereof, wherein, X b , X c , and X d are each independently CH, N, or CR', wherein R' is halogen or C 1-4 alkoxy; ring A is phenyl, pyridinyl, or C 5-6 cycloalkyl; R a are each independently deuterium, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, cyano, amino, aminosulfonyl, methylsulfonyl, -COOC 1-4 alkyl, -C 1-4 alkyl-OH, or carbamoyl; m is 0, 1, 2, 3, or 4; R b is H or C 1-4 alkyl; ring B is 5-6 membered heteroaryl; R c are each independently C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or halogen; n is 0, 1, 2, 3, or 4; ring C is 5-6 membered heteroaryl comprising 1 to 4 N atom(s); R d are each independently C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy; 1 is 0, 1, 2, 3, or 4; and L 1 is C 1-4 alkylene or C 3-6 cycloalkylene.

[0017] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring A is phenyl or 5-6 membered heteroaryl.

[0018] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring A is

[0019] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring A is

[0020] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring A is

[0021] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring A is

[0022] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring A is

[0023] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R' are each independently -OCH 3 or -F.

[0024] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R a are each independently -F, -OCH 3 , -CF 3 , -COOCH 3 , -C(CH 3 ) 2 -OH, -CHF 2 , -CN, -Cl, -NH 2 , CH 3 -NH-S(O) 2 -, or NH 2 -S(O) 2 -.

[0025] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R a are each independently -F, -OCH 3 or -CF 3 .

[0026] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R a are each independently -COOCH 3 , -C(CH 3 ) 2 -OH, or -CHF 2 .

[0027] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R a are each independently -CH 3 , -OH, -Br, -CH 2 CH 3 , CH(CH 3 ) 2 , -OCH(CH 3 ) 2 , D, -CD 3 , or

[0028] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0029] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0030] In some embodiments of the present application, in the compound represented by formula (II') or formula (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0031] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0032] In some embodiments of the present application, in the compound represented by formula (II') or formula (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0033] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0034] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0035] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0036] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0037] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0038] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0039] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0040] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0041] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0042] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0043] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0044] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0045] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0046] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is or wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0047] In some embodiments of the present application, in the compound represented by formula or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0048] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0049] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is or wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0050] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0051] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0052] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0053] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0054] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is or wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0055] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0056] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0057] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0058] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0059] In some embodiments of the present application, in the compound represented by formula (II') or (I'), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is or wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0060] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0061] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0062] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0063] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is or wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0064] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0065] In some embodiments of the present application, in the compound represented by formula (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is or wherein a represents the linking site with ring B, and b represents the linking site with L 1 .

[0066] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R b is hydrogen.

[0067] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring B is

[0068] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring B is

[0069] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring B is

[0070] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring B is

[0071] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R c are each independently CH 3 O-, Cl-, CH(CH 3 ) 2 -, -OCHF 2 , or -CF 3 .

[0072] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R c are each independently -OCH 3 , -CH(CH 3 ) 2 , or -Cl.

[0073] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R c are each independently -CH 3 , or -OCD 3 .

[0074] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0075] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0076] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0077] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is or

[0078] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring C is

[0079] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring C is

[0080] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring C is

[0081] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring C is

[0082] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, ring C is

[0083] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R d are each independently -CF 3 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 2 CH 3 , or -CD 3 .

[0084] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R d are each independently -CF 3 , -CH 3 , or -CH(CH 3 ) 2 .

[0085] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R d are each independently -CH 2 CH 3 .

[0086] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R d are each independently -Cl or

[0087] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, R d are each independently -Br or -F.

[0088] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0089] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0090] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0091] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is

[0092] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, structural unit is or

[0093] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, L 1 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or

[0094] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, L 1 is -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.

[0095] In some embodiments of the present application, in the compound represented by formula (II'), (I'), or (I'-1), or the isomer thereof or the pharmaceutically acceptable salt thereof, L 1 is -CH(C 2 H 5 )- or a chemical bond.

[0096] The present application further provides the following compounds, or isomers or pharmaceutically acceptable salts thereof, wherein R a , R c , R d , R e , L 1 , and m are defined as mentioned above in the present application; and X is C, N, or O.

[0097] The present application further provides the following compound, or an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R a , R c , R d , L 1 , and m are defined as mentioned above in the present application.

[0098] The present application further provides the following compounds, or isomers or pharmaceutically acceptable salts thereof, wherein R a , R c , R d , and m are defined as mentioned above in the present application.

[0099] The present application further provides the following compounds, or isomers or pharmaceutically acceptable salts thereof, wherein R a , R c , R d , R e , and m are defined as mentioned above in the present application; and X is C, N, or O.

[0100] The present application further provides the following compound, or an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R a , R c , R d , R e , and m are defined as mentioned above in the present application.

[0101] The present application further provides the following compounds, or isomers or pharmaceutically acceptable salts thereof,

[0102] In a second aspect, the present application provides a preparation method for the compound:Preparation method I

[0103] wherein, ring A, X b , X c , ring C, R b , R c , and R d are defined as mentioned above in the present application; compound 1' is prepared by reacting SM1 and SM2 under the presence of a base and a catalyst, wherein the base comprises sodium carbonate, potassium carbonate, K 3 PO 4 , Na 2 CO 3 , CsF, Cs 2 CO 3 , t-Bu-Na and the like, and the catalyst comprises Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 and the like; compound 2' is prepared by reacting compound 1' with 1,2-bis(diphenylphosphino)ethane; compound 3' is prepared by a substitution reaction between compound 2' and SM3 under the presence of a base, wherein the base comprises sodium hydride, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide and the like; and compound 4' is prepared by a coupling reaction between compound 3' and SM4 under the presence of a base and a catalyst, wherein the base comprises sodium carbonate, potassium carbonate, K 3 PO 4 , Na 2 CO 3 , CsF, Cs 2 CO 3 , t-Bu-Na and the like, and the catalyst comprises Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 and the like. Preparation method II

[0104] wherein, X b , X c , ring C, R c , R d , and R a are defined as mentioned above in the present application; compound 5' is prepared by reacting SM5 under the presence of a base and a catalyst, wherein the base comprises sodium carbonate, potassium carbonate, K 3 PO 4 , Na 2 CO 3 , CsF, Cs 2 CO 3 , t-Bu-Na and the like, and the catalyst comprises Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 and the like; compound 6' is prepared by reacting compound 5' with 1,2-bis(diphenylphosphino)ethane; compound 7' is prepared by a substitution reaction between compound 6' and SM3 under the presence of a base, wherein the base comprises sodium hydride, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide and the like; and compound 8' is prepared by reacting compound 7' under the presence of a base and a catalyst, wherein the base comprises sodium carbonate, potassium carbonate, K 3 PO 4 , Na 2 CO 3 , CsF, Cs 2 CO 3 , t-Bu-Na and the like, and the catalyst comprises Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 and the like.

[0105] In a third aspect, the present application provides a pharmaceutical composition, comprising a therapeutically effective amount of the compound, or the isomer thereof or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0106] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for the delivery of a biologically active agent to an animal, in particular a mammal. Depending on the mode of administration and the nature of dosage form, the pharmaceutically acceptable carrier comprises, for example, adjuvant, excipient or vehicle, such as diluent, preservative, filler, flow modifier, disintegrating agent, humectant, emulsifier, suspending agent, sweetener, flavoring agent, aromatizer, antibacterial agent, antifungal agent, lubricant, and dispersant. Pharmaceutically acceptable carrier may be formulated based on the capabilities of a person of ordinary skills in the art in view of a large number of factors, including but not limited to: type and nature of active agent being formulated, the subject to which the composition comprising the agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication(s). Pharmaceutically acceptable carrier comprises both aqueous and non-aqueous media and various solid and semi-solid dosage forms. In addition to the active agent, the carrier comprises many different ingredients and additives, and such additional ingredients included in the composition are well known to those of ordinary skill in the art for a variety of reasons (e.g., stabilizing the active agent, binders, etc.).

[0107] A fourth aspect of the present application provides the compound, or the isomer thereof or the pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating related diseases mediated by a USP1 target.

[0108] In some embodiments of the present application, the related diseases mediated by a USP1 target comprise cellular inflammatory diseases, neurodegenerative diseases, and cancers.TECHNICAL EFFECT

[0109] The compound of the present application has significant USP1 enzymatic inhibitory activity and can be used in the treatment of cancer.DESCRIPTION AND DEFINITION

[0110] Unless otherwise indicated, the following terms and phrases used herein are intended to have the meanings set forth below. A particular term or phrase should not be regarded as indefinite or unclear without special definition, but should be understood in its ordinary meaning.

[0111] The term "pharmaceutically acceptable" means those compounds, materials, compositions and / or dosage forms which, within reasonable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, and which have a reasonable benefit / risk ratio.

[0112] The term "pharmaceutically acceptable salt" refers to derivatives of the compound of the application prepared with relatively non-toxic acids or bases. The salt may be prepared during the synthesis, isolation, or purification of the compound, or prepared separately by reacting the free form of a purified compound with a suitable acid or base. When the compound contains a relatively acidic functional group, the salt comprises alkali addition salts obtained by reacting with an alkali metal or alkaline earth metal hydroxid or an organic amine, including cations based on alkali metals and alkaline earth metals, as well as non-toxic ammonium, quaternary ammonium and amine cations, and also salts of amino acids and the like. When the compound contains a relatively basic functional group, the salt comprises acid addition salts obtained by reacting with an organic or inorganic acid.

[0113] The term "excipient" generally refers to the carrier, diluent and / or medium required to formulate an effective pharmaceutical composition.

[0114] The term "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the compound or the pharmaceutically acceptable salt thereof of the present application, to treat a disorder with a reasonable effect / risk ratio suitable for any medical therapy and / or prophylaxis. It should be recognized, however, that the total daily dosage of the compound represented by formula (II') or the pharmaceutically acceptable salt thereof or the composition of the present application is subject to the decision of the attending physician within the bounds of sound medical judgment. For any particular patient, the specific therapeutically effective amount level shall be based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; the medicament that is administrated in combination with or simultaneously with the specific compound employed; and similar factors that are well known in the medical field. For example, it is a practice in the art to start the dosage of a compound at a level below that required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained.

[0115] Unless otherwise specified, the term "5-10 membered heteroaryl" refers to a monocyclic or bicyclic group having a conjugated π-electron system composed of 5 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatom(s) independently selected from the group consisting of O, S, and N, the rest of them being carbon atoms. Among them, each N atom is optionally quaternized, and each N and S heteroatom is optionally oxidized (i.e., NO and S(O) p , p being 1 or 2). The 5-6 membered heteroaryl may be attached to other moieties of the compound via the heteroatom or the carbon atom. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (comprising N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (comprising 2-pyrazolyl, 3-pyrazolyl, and the like), imidazolyl (comprising N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, and the like), oxazolyl (comprising 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, and the like), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, and the like), tetrazolyl, isoxazolyl (comprising 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), thiazolyl (comprising 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, and the like), furanyl (comprising 2-furanyl, 3-furanyl, and the like), thienyl (comprising 2-thienyl, 3-thienyl, and the like), pyridinyl, pyrimidinyl, benzimidazolyl, and the like.

[0116] Unless otherwise specified, the term "fused-heterocyclyl" refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more ring structures sharing two adjacent atoms with each other and containing at least one heteroatom as ring atom; the heteroatom is generally N, O, or S; the carbon ring atoms and the heteroatoms in the fused-heterocyclyl may be further oxidized to form cyclic moieties containing C(O), NO, SO, or S(O) 2 groups, which are also encompassed within the definition of heterocyclyl as described in the present application. The term "non-aromatic" in this definition means that the group is not aromatic when it exists on its own. The 11-14 membered fused-heterocyclyl as defined in the present application comprises "11-14 membered saturated fused-heterocyclyl" and "11-14 membered partially saturated fused-heterocyclyl". The fused-heterocyclyl may be 5-6 membered heterocyclyl fused with 5-6 membered heterocyclyl, 5-6 membered heterocyclyl fused with 5-6 membered cycloalkyl, phenyl fused with 5-6 membered heterocyclyl, phenyl fused with 5-6 membered saturated heterocyclyl, 5-6 membered heteroaryl fused with 5-6 membered heterocyclyl, 5-6 membered heteroaryl fused with 5-6 membered saturated heterocyclyl, phenyl fused with 5-6 membered heterocyclyl and fused with 5-6 membered heterocyclyl, 5-6 membered heteroaryl fused with 5-6 membered heterocyclyl and fused with 5-6 membered heterocyclyl, phenyl fused with 5-6 membered cycloalkyl and fused with 5-6 membered heterocyclyl, 5-6 membered heteroaryl fused with 5-6 membered cycloalkyl and fused with 5-6 membered heterocyclyl; specific examples of the fused-heterocyclyl include, but are not limited to:

[0117] Unless otherwise specified, the term "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated non-aromatic ring comprising 1-3 heteroatoms selected from N, O and S. Any carbon group(s) or heteroatom(s) in the heterocyclyl may be oxo-substituted, e.g., the carbon group may form -C(O)-. The "heterocyclyl" of the present application refers to a non-aromatic cyclic group containing at least one heteroatom as ring atom(s), which is derived from the removal of a hydrogen atom. Heterocyclyl comprises a saturated or partially saturated monocyclic heterocyclyl; and the heterocyclyl is independent of the linking site (i.e., it can be linked by either a carbon atom or a heteroatom). Examples of "heterocyclyl" include, but are not limited to,

[0118] Unless otherwise specified, the term "cycloalkyl" refers to a saturated monocyclic or multicyclic hydrocarbyl group. The cycloalkyl is preferably C 3-12 cycloalkyl, more preferably C 3-8 cycloalkyl, further preferably C 5-6 cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopentyl and cyclohexyl.

[0119] Unless otherwise specified, the term "cycloalkylene" refers to a divalent group formed by further removal of a hydrogen atom from a cycloalkyl.

[0120] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0121] Unless otherwise specified, the term "C 1-4 alkyl" refers to a saturated hydrocarbyl group with a C 1-4 straight or branched chain. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and the like.

[0122] Unless otherwise specified, the term "alkylene" refers to a straight or branched saturated aliphatic hydrocarbon group which is a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or from two different carbon atoms. Alkylene may be a straight or branched group comprising from 1 to 20 carbon atoms, preferably from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably from 1 to 4 carbon atoms. Alkylene includes, but is not limited to, methylene (-CH 2 -), 1,1-ethylidene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 -), 1,1-propylidene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like.

[0123] Unless otherwise specified, the term "C 1-4 haloalkyl" refers to an alkyl group in which one or more hydrogen atom(s) has been replaced by halogen atom(s). Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0124] Unless otherwise specified, the term "C 1-4 alkoxy" refers to a C 1-4 alkyl group linked by an oxygen bridge. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy.

[0125] Unless otherwise specified, the term "-C 1-4 alkyl-OH" refers to a C 1-4 alkyl having a hydroxyl substituent. Examples include, but are not limited to, -CH 2 -OH, -(CH 2 ) 2 -OH, and -CH(CH 3 ) 2 -OH.

[0126] Unless otherwise specified, the term "C 3-6 cycloalkyl" refers to a 3-6 membered monocycloalkyl. Examples of such monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0127] Unless otherwise specified, the term "5-6 membered heteroaryl comprising 1 to 4 N atom(s)" refers to a 5-6 membered heteroaryl in which carbon atom(s) in the ring is / are replaced by 1, 2, 3 or 4 nitrogen atoms. Examples include, but are not limited to,

[0128] Unless otherwise specified, in the structure "- - -" refers to a single bond or a double bond.BRIEF DESCRIPTION OF THE DRAWINGS

[0129] The accompanying drawings illustrated herein are provided for further understanding of the present application and form part of the present application, and the schematic embodiments of the present application and related description are used to explain the present application and do not constitute an undue limitation of the present application. FIG. 1 shows tumor growth in mice in groups G1 to G4 in Test Example 5 of the present application. FIG. 2 shows the change in body weight of mice in groups G1 to G4 in Test Example 5 of the present application. DETAILED DESCRIPTION OF THE INVENTION

[0130] For the sake of clarity of the purpose, technical solutions and advantages of the present application, the application is further described in detail by referring to the drawings and examples. Obviously, the described examples are only a part of the examples of the present application, rather than all the examples. All other examples obtained by those of ordinary skills in the art based on the present application shall fall within the protection scope of this application.

[0131] The compounds of the present application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments enumerated below, embodiments resulting from combinations thereof with other methods of chemical synthesis, and equivalent substitutions known to those skilled in the art, with preferred embodiments including, but not limited to, the embodiments of the present application.

[0132] The solvents used in this application are commercially available.

[0133] The structures of the compounds of the present application are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was determined using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), and heavy water (D 2 O), and the internal standard was tetramethylsilane (TMS).

[0134] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole mass spectrometer (ion source was provided by electrospray ionization).

[0135] Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) was perfromed using a Waters UPLC H-class SQD mass spectrometer (ion source was provided by electrospray ionization).

[0136] HPLC was performed using a Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0137] Preparative HPLC was performed using Waters 2555-2489 (10 µm, ODS 250 cm × 5 cm) or GILSON Trilution LC.

[0138] Chiral HPLC was performed using Waters acquity UPC2; and the column was a Daicel chi ring Clpak AD-H (5 µm, 4.6 × 250 mm).

[0139] Supercritical fluid chromatography (SFC) was performed using Waters SFC 80Q.

[0140] The starting materials in the examples of the present application are known and commercially available, or can be synthesized using or according to methods known in the art.

[0141] Unless otherwise specified, all reactions of this application are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature in degrees Celsius (°C).

[0142] The present application will be described in more details by way of examples, which, however, does not imply any unfavorable limitation of the present application. The compounds of the present application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments enumerated below, embodiments resulting from combinations thereof with other methods of chemical synthesis, and equivalent substitutions known to those skilled in the art, with preferred embodiments including, but not limited to, the embodiments of the present application. Various variations and improvements to the specific examples of the present application without departing from the spirit and scope of the present application will be apparent to those skilled in the art.I. Preparation method

[0143] As used herein, room temperature refers to a temperature of about 20°C to 30°C.Intermediate INT-1: (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0144]

[0145] Step A: At room temperature, 3,3-dibromo-1,1,1-trifluoropropan-2-one (144 g, 0.54 mol) and sodium acetate (80 g, 0.97 mol) were dissolved in water (320 mL). Subsequently, the above solution was warmed up to 90°C and stirred for 0.5 hour. Then the reaction system was cooled to 0°C, and methyl 4-formylbenzoate (80 g, 0.49 mol) and a mixture of 28 wt% aqueous ammonia (400 mL) and methanol (120 mL) were slowly added dropwise to the above reaction solution. Finally the reaction system was continued to be stirred at room temperature for 16 hours.

[0146] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filter cake was rinsed with ethyl acetate (100 mL × 3 times). The filtrate was then collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 104 g of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate.

[0147] MS (ESI) M / Z: 271.0 [M+H] +< .

[0148] Step B: At room temperature, methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (69 g, 0.25 mol) and cesium carbonate (250 g, 0.76 mol) were dissolved in acetonitrile (1.2 L) and stirred for 2 hours. Subsequently, 2-iodopropane (64.9 g, 0.38 mol) was added to the above solution, and the reaction system was heated to 50°C and stirred for 24 hours. The reaction system was then cooled to 0°C and further 2-iodopropane (21.6 g, 0.13 mol) was added. Then the reaction system was stirred at 50°C for 4 hours.

[0149] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (1.5 L), and the mixture was extracted with ethyl acetate (500 mL × 3 times). Organic phases were combined and then washed with saturated saline (150 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 33 g of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate.

[0150] MS (ESI) M / Z: 313.2 [M+H] +< .

[0151] Step C: At room temperature and under nitrogen protection, methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (33 g, 0.11 mol) was dissolved in dry tetrahydrofuran (528 mL). Subsequently, 2.5 M (mol / L) lithium aluminum hydride solution (85 mL, 0.22 mol) was slowly added to the above solution dropwise at 0°C. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0152] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by slowly adding to ice water (1 L) dropwise. The resultant was filtered and the filter cake was washed with ethyl acetate (100 mL × 3 times). The filtrate was extracted with ethyl acetate (500 mL × 3 times), and organic phases were combined and then washed with saturated saline (150 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 28 g of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol.

[0153] MS (ESI) M / Z: 285.1 [M+H] +< .

[0154] 1< H NMR (400 MHz, CDCl 3 ): δ 7.47 - 7.32 (m, 5H), 4.72 (s, 2H), 4.59 - 4.46 (m, 1H), 2.97 (br, 1H), 1.44 (d, J = 6.8 Hz, 6H).Intermediate INT-2: 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

[0155]

[0156] Step A: At room temperature, (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (700 mg, 2.46 mmol) was dissolved in dichloromethane (12.5 mL). Then, triphenylphosphine (1.29 g, 4.93 mmol), sodium bicarbonate (414 mg, 4.93 mmol) and carbon tetrabromide (1.63 g, 4.93 mmol) were added sequentially to the above solution. Then the reaction system was continued to be stirred at room temperature for 2 hours.

[0157] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (20 mL), and the mixture was extracted with dichloromethane (10 mL × 3 times). Organic phases were combined and then washed with saturated saline (60 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 820 mg of 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole.

[0158] MS (ESI) M / Z: 347.2 [M+H] +< .Intermediate INT-3: (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid

[0159]

[0160] Step A: At room temperature and under nitrogen protection, compound 4-chloro-6-methoxypyrimidine (25 g, 172.94 mmol), cyclopropylboronic acid (25.25 g, 294 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (6.3 g, 8.68 mmol), potassium phosphate (73.42 g, 345.88 mmol) and silver oxide (20.04 g, 86.47 mmol) were dissolved in 1,4-dioxane (868 mL). The above solution was then heated to 90°C and stirred for 16 hours.

[0161] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered while hot and the filtrate was concentrated under reduced pressure. The resulting residue was quenched by adding water (500 mL), and the mixture was extracted with dichloromethane (100 mL × 3 times). Organic phases were combined and then washed with saturated saline (150 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 18.3 g of 4-cyclopropyl-6-methoxypyrimidine.

[0162] MS (ESI) M / Z: 151.2 [M+H] +< .

[0163] Step B: At -20°C and under nitrogen protection, 4-cyclopropyl-6-methoxypyrimidine (45 g, 299.64 mmol) was dissolved in ethanol (1.5 L). Subsequently, liquid bromine (240 g, 1.5 mol) was slowly added dropwise to the above solution. Then the reaction system was continued to be stirred at room temperature for 16 hours.

[0164] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated through reduced pressure distillation. The resulting crude product was pulped with ethyl acetate and filtered, and the filter cake was collected. Then the filter cake was added to water (150 mL) and stirred at 0°C, and saturated sodium bicarbonate solution was added dropwise to the solution system until pH=7. Finally, the mixture was filtered, the filter cake was rinsed with water (150 mL × 2 times), the filter cake was collected and concentrated under reduced pressure to obtain 56 g of 5-bromo-4-cyclopropyl-6-methoxypyrimidine.

[0165] MS (ESI) M / Z: 230.1 [M+H] +< .

[0166] 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 3.99 (s, 3H), 2.50 - 2.44 (m, 1H), 1.16 - 1.09 (m, 2H), 1.08 - 1.02 (m, 2H).

[0167] Step C: At room temperature and under nitrogen protection, 5-bromo-4-cyclopropyl-6-methoxypyrimidine (15.0 g, 65.79 mmol) and triisopropyl borate (16.08 g, 85.53 mmol) were dissolved in toluene / tetrahydrofuran (150 mL / 45 mL). Subsequently, the above reaction solution was cooled to -78°C, stirred for 30 min, 2.5 M n-butyllithium solution (34.2 mL, 85.53 mmol) was slowly added dropwise, and the mixture was stirred for 30 min. Then the reaction system was warmed to -20°C and stirred for 1 hour.

[0168] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (100 L). The mixed solution was then filtered and the filter cake was rinsed with water (20 mL × 3 times) to obtain 9.7 g of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid.

[0169] MS (ESI) M / Z: 195.0 [M+H] +< .Intermediate INT-4: 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0170]

[0171] Step A: At room temperature, methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (5 g, 18.45 mmol) and potassium carbonate (5.1 g, 36.7 mmol) were dissolved in N,N-dimethylformamide (92 mL). The reaction system was then cooled to 0°C, and iodomethane (3.14 g, 22.14 mmol) was slowly added dropwise. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0172] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (200 mL), and the mixture was extracted with ethyl acetate (60 mL × 3 times). Organic phases were combined and then washed with saturated saline (100 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.2 g of methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate.

[0173] MS (ESI) M / Z: 285.0 [M+H] +< .

[0174] Step B: At room temperature, methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (3.2 g, 11.26 mmol) was dissolved in tetrahydrofuran (28 mL). The reaction system was then cooled to 0°C, and then lithium aluminum hydride (2.14 g, 56.32 mmol) was slowly added dropwise. Then the reaction system was continued to be stirred at room temperature for 2 hours.

[0175] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (100 mL), and the mixture was extracted with ethyl acetate (60 mL × 3 times). Organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.6 g of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol.

[0176] MS (ESI) M / Z: 257.0 [M+H] +< .

[0177] Step C: At room temperature and under nitrogen protection, (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (2.6 g, 10.12 mmol), sodium bicarbonate (1.7 g, 20.24 mmol), and triphenylphosphine (5.3 g, 20.24 mmol) were dissolved in dichloromethane (51 mL). The reaction system was then cooled to 0°C and then carbon tetrabromide (6.7 g, 20.24 mmol) was slowly added. Then the reaction system was warmed to room temperature and continued to be stirred for 2 hours.

[0178] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (100 mL), and the mixture was extracted with dichloromethane (50 mL × 3 times). Organic phases were combined and then washed with saturated saline (80 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.4 g of (2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole.

[0179] MS (ESI) M / Z: 319.0 [M+H] +< .Intermediate INT-5: 2-(4-(bromomethyl)phenyl)-1-ethyl-4-(trifluoromethyl)-1H-imidazole

[0180]

[0181] Step A: At 0°C and under nitrogen protection, methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (700 mg, 2.59 mmol) and sodium hydride (156 mg, 3.89 mmol) were dissolved in N,N-dimethylformamide (13 mL), and the mixture was stirred for 30 minutes. Then iodoethane (606.6 mg, 3.89 mmol) was slowly added dropwise to the above system, and the reaction system was warmed room temperature and stirred for 1 hour.

[0182] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (60 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 300 mg of methyl 4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate.

[0183] MS (ESI) M / Z: 299.0 [M+H] +< .

[0184] Step B: In an ice-water bath and under nitrogen protection, methyl 4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (300 mg, 1.00 mmol) was dissolved in dry tetrahydrofuran (5 mL). Subsequently, lithium aluminium hydride (0.8 mL, 2.00 mmol) was added to the above solution slowly, and the reaction system was warmed to room temperature and stirred for 2 hours.

[0185] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (10 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 210 mg of (4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol.

[0186] MS (ESI) M / Z: 271.0 [M+H] +< .

[0187] Step C: In an ice-water bath and under nitrogen protection, (4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (200 mg, 0.74 mmol), triphenylphosphine (390 mg, 1.48 mmol), sodium bicarbonate (125 mg, 1.48 mmol) and carbon tetrabromide (390 mg, 1.48 mmol) were dissolved in dichloromethane (3.7 mL). Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0188] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (50 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 230 mg of 2-(4-(bromomethyl)phenyl)-1-ethyl-4-(trifluoromethyl)-1H-imidazole.

[0189] MS (ESI) M / Z: 333.0 [M+H] +< .Intermediate INT-6: 2-chloro-9H-pyrimido[4,5-b]indole

[0190]

[0191] Step A: At room temperature, 1-bromo-2-nitrobenzene (500 mg, 2.49 mmol), (2-chloropyrimidin-5-yl)boronic acid (590 mg, 3.74 mmol), sodium carbonate (792 mg, 7.47 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (305 mg, 0.37 mmol) were dissolved in 1,4-dioxane / water (11 mL / 1.4 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 3 h under nitrogen protection.

[0192] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (20 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (15 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 500 mg of 2-chloro-5-(2-nitrophenyl)pyrimidine.

[0193] MS (ESI) M / Z: 236.0 [M+H] +< .

[0194] Step B: At room temperature, 2-chloro-5-(2-nitrophenyl)pyrimidine (500 mg, 2.13 mmol) and 1,2-bis(diphenylphosphino)ethane (1.06 g, 2.66 mmol) were dissolved in 1,2-dichlorobenzene (7.1 mL). Then the reaction system was stirred at 160°C for 1 hour.

[0195] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (10 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 200 mg of 2-chloro-9H-pyrimido[4,5-b]indole.

[0196] MS (ESI) M / Z: 204.0 [M+H] +< .Intermediate INT-7: 2-chloro-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidine

[0197]

[0198] Step A: At room temperature, 4-amino-5-bromo-2-chloropyrimidine (1.0 g, 4.83 mmol), 1-cyclopentenylboronic acid pinacol ester (1.4 g, 7.25 mmol), potassium phosphate (2.6 g, 12.08 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (389 mg, 0.48 mmol) were dissolved in 1,4-dioxane / water (15 mL / 3 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 3 hours under nitrogen protection.

[0199] After the disappearance of raw materials as monitored by TLC, the reaction solution was quenched by adding to ice water (20 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (15 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography to obtain 600 mg of 2-chloro-5-(cyclopent-1-en-1-yl)pyrimidin-4-amine.

[0200] MS (ESI) M / Z: 196.1 [M+H] +< .

[0201] 1< H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.29 (br, 2H), 6.09 (t, J = 2.2 Hz, 1H), 2.65 - 2.57 (m, 2H), 2.49 - 2.43 (m, 2H), 1.91 (p, J = 7.5 Hz, 2H).

[0202] Step B: At 0°C, 2-chloro-5-(cyclopent-1-en-1-yl)pyrimidin-4-amine (100 mg, 0.51 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL). N-bromosuccinimide (100 mg, 0.56 mmol) was then added, and the mixture was stirred for 1 hour. Subsequently, 2M aqueous sodium hydroxide solution (0.2 mL) was added, and the mixture was stirred for 30 minutes.

[0203] After the disappearance of raw materials as monitored by TLC, the reaction solution was quenched by adding ice water (10 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. To the residue was added tetrahydrofuran (3 mL) followed by boron trifluoride ether (217 mg, 1.53 mmol), and the mixture was stirred at 60°C for 3 hours.

[0204] After the disappearance of raw materials as monitored by TLC, the reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (50 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography to obtain 60 mg of 2-chloro-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidine.

[0205] MS (ESI) M / Z: 194.1 [M+H] +< .

[0206] 1< H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.68 (s, 1H), 2.87 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.48 - 2.39 (m, 2H).Intermediate INT-8: 2-(4-(bromomethyl)-2-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)- 1H-imidazole

[0207]

[0208] Step A: At room temperature, 3,3-dibromo-1,1,1-trifluoropropan-2-one (40.2 g, 0.15 mol) and sodium acetate (12.25 g, 0.15 mol) were dissolved in water (36 mL). Subsequently, the above solution was warmed up to 90°C and stirred for 0.5 hour. Then the reaction system was cooled to 0°C, and methyl 4-formyl-3-methoxybenzoate (10 g, 51.54 mmol) and a mixture of 28 wt% aqueous ammonia (45 mL) and methanol (135 mL) were slowly added dropwise to the above reaction solution. Finally, the reaction system was continued to be stirred at room temperature for 16 hours.

[0209] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filter cake was rinsed with ethyl acetate / petroleum ether (v / v, 3 / 1). The filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 10.85 g of methyl 3-methoxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate.

[0210] MS (ESI) M / Z: 301.0 [M+H] +< .

[0211] Step B: At room temperature, methyl 3-methoxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (6 g, 0.02 mol) and cesium carbonate (19.7 g, 0.06 mol) were dissolved in acetonitrile (65 mL), and the solution was stirred for 2 hours. Subsequently, 2-iodopropane (5.1 g, 0.03 mol) was added to the above solution, and the reaction system was heated to 50°C and stirred for 24 hours. The reaction system was then cooled to 0°C and further 2-iodopropane (5.1 g, 0.03 mol) was added. The reaction system was heated to 50°C and stirred for 4 hours.

[0212] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (300 mL), and the mixture was extracted with ethyl acetate (100 mL × 3 times). Organic phases were combined and then washed with saturated saline (50 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6.9 g of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methoxybenzoate.

[0213] MS (ESI) M / Z: 343.0 [M+H] +< .

[0214] Step C: At 0°C and under nitrogen protection, methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methoxybenzoate (2.9 g, 8.48 mmol) was dissolved in dry tetrahydrofuran (30 mL). Subsequently, lithium aluminium hydride (6.8 mL, 17 mmol) was slowly added to the above solution dropwise. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0215] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by slowly adding to ice water (100 mL) dropwise. The resultant was filtered and the filter cake was rinsed with ethyl acetate (50 mL × 3 times). The filtrate was extracted with ethyl acetate (50 mL × 3 times), and organic phases were combined and then washed with saturated saline (150 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.95 g of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methoxyphenyl)methanol.

[0216] MS (ESI) M / Z: 315.4 [M+H] +< .

[0217] Step D: At 0°C, (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methoxyphenyl)methanol (500 mg, 1.59 mmol), sodium bicarbonate (269 mg, 3.2 mmol), and triphenylphosphine (840 mg, 3.2 mmol) were dissolved in dry dichloromethane (8 mL). Subsequently, carbon tetrabromide (1.06 g, 3.2 mmol) was slowly added to the above reaction solution. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0218] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (50 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 350 mg of 2-(4-(bromomethyl)-2-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole.

[0219] MS (ESI) M / Z: 377.2 [M+H] +< .Intermediate INT-9: 2-(4-(bromomethyl)-2-fluoro-6-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazol e

[0220]

[0221] Step A: At room temperature, 4-bromo-2-fluoro-6-methoxybenzaldehyde (4 g, 17 mmol), triethylamine (12.38 g, 0.12 mol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.34 g, 18 mmol) were dissolved in methanol (120 mL). The reaction system was evacuated to remove air and purged with carbon monoxide for 3 times, and then the reaction solution was heated to 90°C and stirred for 24 hours.

[0222] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.98 g of methyl 3-fluoro-4-formyl-5-methoxybenzoate.

[0223] MS (ESI) M / Z: 213.0 [M+H] +< .

[0224] Step B: At room temperature, 3,3-dibromo-1,1,1-trifluoropropan-2-one (6.72 g, 25 mmol) and sodium acetate (2.06 g, 25 mmol) were dissolved in water (7 mL). Subsequently, the above solution was warmed up to 90°C and stirred for 0.5 hour. Then the reaction system was cooled to 0°C, and methyl 3-fluoro-4-formyl-5-methoxybenzoate (1.98 g, 9 mmol) and a mixture of 28 wt% aqueous ammonia (17 mL) and methanol (45 mL) were slowly added dropwise to the above reaction solution.

[0225] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filter cake was rinsed with ethyl acetate / petroleum ether (v / v, 3 / 1). The filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.06 g of methyl 3-fluoro-5-methoxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate.

[0226] MS (ESI) M / Z: 319.0 [M+H] +< .

[0227] Step C: At room temperature, methyl 3-fluoro-5-methoxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2.06 g, 6.5 mmol) and cesium carbonate (6.31 g, 19 mmol) were dissolved in acetonitrile (25 mL) and stirred for 2 hours. Subsequently, 2-iodopropane (1.65 g, 9.7 mmol) was added to the above solution, and the reaction system was heated to 50°C and stirred for 24 hours. The reaction system was then cooled to 0°C and further 2-iodopropane (1 g, 5.9 mmol) was added. The reaction system was heated to 50°C and stirred for 4 hours.

[0228] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (50 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (50 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.84 g of methyl 3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-5-methoxybenzoate.

[0229] MS (ESI) M / Z: 361.0 [M+H] +< .

[0230] Step D: At 0°C and under nitrogen protection, methyl 3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-5-methoxybenzoate (1.84 g, 5.1 mmol) was dissolved in dry tetrahydrofuran (25 mL). Subsequently, lithium aluminum hydride solution (4.2 mL, 0.01 mol) was slowly added to the above solution dropwise. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0231] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by slowly adding to ice water (100 mL) dropwise. The resultant was filtered and the filter cake was rinsed with ethyl acetate (50 mL × 3 times). The filtrate was extracted with ethyl acetate (50 mL × 3 times), and organic phases were combined and then washed with saturated saline (150 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.38 g of (3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-5-methoxyphenyl)methanol.

[0232] MS (ESI) M / Z: 333.2 [M+H] +< .

[0233] Step E: At 0°C and under nitrogen protection, (3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-5-methoxyphenyl)methanol (500 mg, 1.5 mmol), sodium bicarbonate (269 mg, 3.2 mmol), and triphenylphosphine (840 mg, 3.2 mmol) were dissolved in dry dichloromethane (8 mL). Subsequently, liquid bromine (1.06 g, 3.2 mmol) was slowly added to the above solution. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0234] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (50 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 350 mg of 2-(4-(bromomethyl)-2-fluoro-6-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole.

[0235] MS (ESI) M / Z: 395.2 [M+H] +< .Intermediate INT-10: 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0236]

[0237] Step A: At room temperature, 4-chloro-1H-pyrazole (5 g, 0.049 mol), 2-iodopropane (20 g, 0.118 mol) and cesium carbonate (33 g, 0.1 mol) were dissolved in acetonitrile (40 mL). Then the reaction system was stirred at 80°C for 2 hours.

[0238] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (100 mL), and the mixture was extracted with ethyl acetate (50 mL × 3 times). Organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.62 g of 4-chloro-1-isopropyl-1H-pyrazole.

[0239] MS (ESI) M / Z: 145.2 [M+H] +< .

[0240] Step B: At 0°C and under nitrogen protection, 4-chloro-1-isopropyl-1H-pyrazole (2 g, 0.014 mol) was dissolved in tetrahydrofuran (14 mL). Subsequently, n-butyllithium (11.2 mL, 0.017 mol) was added to the above solution dropwise, and the reaction system was warmed to room temperature and stirred for 1 hour. The reaction solution was then cooled to -78°C and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.45 g, 0.018 mol) was slowly added dropwise, and the mixture was heated to room temperature and stirred for 2 hours.

[0241] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding saturated ammonium chloride aqueous solution (40 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.4 g of 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0242] MS (ESI) M / Z: 271.0 [M+H] +< .Intermediate INT-11: 2-(4-(1-bromopropyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

[0243]

[0244] Step A: At 0°C and under nitrogen protection, methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (300 mg, 0.96 mmol) was dissolved in dry tetrahydrofuran (5 mL). Subsequently, tetraisopropyl titanate (327 mg, 1.15 mmol) and ethylmagnesium bromide (0.46 mL, 1.15 mmol) were sequentially added to the above solution, and then the reaction system was continued to be stirred for 16 hours at room temperature.

[0245] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (30 mL), and the mixture was filtrated, and then filtrate was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 220 mg of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)propan-1-ol.

[0246] MS (ESI) M / Z: 313.2 [M+H] +< .

[0247] Step B: At 0°C and under nitrogen protection, 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)propan-1-ol (220 mg, 0.71 mmol), triphenylphosphine (372 mg, 1.42 mmol), and sodium bicarbonate (119 mg, 1.42 mmol) were dissolved in dichloromethane (4 mL). Subsequently, carbon tetrabromide (471 mg, 1.42 mmol) was slowly added to the above reaction solution. Then the reaction system was continued to be stirred at room temperature for 30 minutes.

[0248] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (50 mL). The mixed solution was extracted with dichloromethane (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg of 2-(4-(1-bromopropyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole.

[0249] MS (ESI) M / Z: 375.0 [M+H] +< .Intermediate INT-12: 8-(bromomethyl)-2-(trifluoromethyl)imidazo[2,1-a]isoquinoline

[0250]

[0251] Step A: At room temperature, methyl 2-(trifluoromethyl)imidazo[2,1-a]isoquinoline-8-formate (52 mg, 0.18 mmol) was dissolved in tetrahydrofuran (0.9 mL). Subsequently, lithium aluminum hydride solution (0.14 mL, 0.35 mmol) was slowly added to the above solution at 0°C. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0252] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding slowly to ice water (20 mL). The resultant was filtrated, and the filtrate was extracted with ethyl acetate (10 mL × 3 times), and organic phases were combined. Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 32 mg of (2-(trifluoromethyl)imidazo[2,1-a]isoquinolin-8-yl)methanol.

[0253] MS (ESI) M / Z: 267.2 [M+H] +< .

[0254] Step B: At room temperature, methyl (2-(trifluoromethyl)imidazo[2,1-a]isoquinolin-8-yl)methanol (53 mg, 0.20 mmol) was dissolved in dichloromethane (1 mL). Then, triphenylphosphine (157.4 mg, 0.60 mmol), sodium bicarbonate (33.6 mg, 0.40 mmol) and carbon tetrabromide (199 mg, 0.60 mmol) were added sequentially to the above solution at 0°C. Then the reaction system was continued to be stirred at room temperature for 1.5 hours.

[0255] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (20 mL). The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 37.8 mg of 8-(bromomethyl)-2-(trifluoromethyl)imidazo[2,1-a]isoquinoline.

[0256] MS (ESI) M / Z: 329.0 [M+H] +< .Intermediate INT-13: (2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]diaza-9-yl)methanol

[0257]

[0258] Step A: At room temperature, 3,3-dibromo-1,1,1-trifluoropropan-2-one (17.5 g, 65.35 mmol) and sodium acetate (5.35 g, 65.35 mmol) were dissolved in water (19.8 mL), and the solution was stirred at 90°C for 1 hour. The above reaction solution was then cooled down to 0°C, and methyl 5-formyl-1H-pyrrole-2-carboxylate (10 g, 65.35 mmol) in a mixed solution of aqueous ammonia / methanol (59.5 mL / 178 mL) was added. Then the reaction system was stirred for 18 hours at room temperature.

[0259] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the resulting concentrated solution was added with ice water (200 mL). The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and organic phases were combined and then washed with saturated saline (90 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 5.9 g of methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)-1H-pyrrole-2-carboxylate.

[0260] MS (ESI) M / Z: 260.0 [M+H] +< .

[0261] Step B: At room temperature, methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)-1H-pyrrole-2-carboxylate (2.6 g, 10.25 mmol) and cesium carbonate (10 g, 30.76 mmol) were dissolved in acetonitrile (50 mL), and the solution was stirred for 2 hours. Subsequently, 1,3-diiodopropane (4.5 g, 15.3 mmol) was added to the above solution, and the reaction system was heated to 50°C and stirred for 48 hours.

[0262] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the resulting residue was quenched by adding ice water (100 mL), and the mixture was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 1.4 g of methyl 2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]diaza-9-yl)formate was obtained.

[0263] MS (ESI) M / Z: 300.1 [M+H] +< .

[0264] Step C: At room temperature, methyl 2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]diaza-9-yl)formate (1.4 g, 4.68 mmol) was dissolved in tetrahydrofuran (23 mL). Subsequently, lithium aluminum hydride solution (3.74 mL, 9.36 mmol) was slowly added to the above solution at 0°C. Then the reaction system was continued to be stirred at room temperature for 0.5 hour.

[0265] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (40 mL) slowly, and the mixture was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 680 mg of (2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]diaza-9-yl)methanol.

[0266] MS (ESI) M / Z: 272.1 [M+H] +< .Intermediate INT-14: (2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-8-yl)methanol

[0267]

[0268] Step A: At room temperature, methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)-1H-pyrrole-2-carboxylate (2 g, 7.72 mmol) and cesium carbonate (7.54 g, 23.15 mmol) were dissolved in acetonitrile (50 mL) and stirred for 2 hours. Subsequently, 1, 2-dibromoethane (1.45 g, 7.72 mmol) was added to the above solution. Then the reaction system was stirred at 50°C for 48 hours.

[0269] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the resulting residue was quenched by adding ice water (100 mL), and the mixture was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 860 mg of methyl 2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-8-formate was obtained.

[0270] MS (ESI) M / Z: 286.2 [M+H] +< .

[0271] Step B: At room temperature, methyl 2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-8-formate (850 mg, 2.98 mmol) was dissolved in dry tetrahydrofuran (30 mL). Subsequently, lithium aluminum hydride solution (2.24 mL, 4.47 mmol) was slowly added to the above solution at 0°C. Then the reaction system was continued to be stirred at room temperature for 0.5 hour.

[0272] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (40 mL) slowly, and the mixture was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 590 mg of (2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-8-yl)methanol.

[0273] MS (ESI) M / Z: 258.2 [M+H] +< .

[0274] 1< H NMR (400 MHz, DMSO-d6):δ7.82 (d, J = 1.2 Hz, 1H), 6.50 (d, J = 3.6 Hz, 1H), 6.11 (d, J = 3.6 Hz, 1H), 5.10 (t, J = 5.2 Hz, 1H), 4.48 (d, J = 5.2 Hz, 2H), 4.39 - 4.33 (m, 2H), 4.32 - 4.276 (m, 2H).Intermediate INT-15: 7-(bromomethyl)-2-(trifluoromethyl)-5H-imidazo[2,1-a]isoindole

[0275]

[0276] Step A: At room temperature, 3,3-dibromo-1,1,1-trifluoropropan-2-one (55.5 g, 205.72 mmol) was dissolved in water (65 mL). Subsequently, sodium acetate (16.9 g, 205.72 mmol) was added to the above solution, and the reaction system was heated to 90°C and stirred for 1 hour. Then the above solution was cooled down to 0°C, and methyl 5-bromo-2-formylbenzoate (25 g, 102.86 mmol) in a mixed solution of methanol (685 mL) and aqueous ammonia (150 mL) was added slowly and dropwise. Then the reaction system was stirred at 100°C for 2 hours.

[0277] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the resulting concentrated solution was quenched by adding water (100 mL). The mixed solution was extracted with ethyl acetate (200 mL × 3 times), and organic phases were combined and then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was pulped to obtain 41 g of 5-bromo-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoic acid.

[0278] MS (ESI) M / Z: 334.9 [M+H] +< .

[0279] Step B: At 0°C, 5-bromo-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoic acid (36 g, 107.78 mmol) was dissolved in dry tetrahydrofuran (500 mL). Subsequently, borane in tetrahydrofuran (216 mL, 215.27 mmol) was slowly added to the above solution dropwise. Then the reaction system was continued to be stirred at room temperature for 2 hours.

[0280] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (200 mL). The mixed solution was extracted with ethyl acetate (300 mL × 3 times), and organic phases were combined and then washed with saturated saline (300 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 12.3 g of (5-bromo-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol.

[0281] MS (ESI) M / Z: 321.0 [M+H] +< .

[0282] Step C: At 0°C, (5-bromo-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (12.3 g, 38.44 mmol) was dissolved in dichloromethane (192 mL). Subsequently, triethylamine (10.7 mL, 76.88 mmol) and methanesulfonyl chloride (6.6 g, 57.66 mmol) were added sequentially to the above solution. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0283] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (200 mL). The mixed solution was extracted with ethyl acetate (200 mL × 3 times), and organic phases were combined and then washed with saturated saline (200 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 14.5 g of 5-bromo-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzylmesylate.

[0284] MS (ESI) M / Z: 399.0 [M+H] +< .

[0285] Step D: At room temperature, 5-bromo-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzylmesylate (14.5 g, 42.90 mmol) was dissolved in N,N-dimethylformamide (214 mL). Subsequently, cesium carbonate (16.8 g, 51.48 mmol) was added to the above solution. Then the reaction system was stirred at 50°C for 1 hour.

[0286] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (600 mL). The mixed solution was extracted with ethyl acetate (200 mL × 3 times), and organic phases were combined and then washed with saturated saline (200 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.83 g of 7-bromo-2-(trifluoromethyl)-5H-imidazo[2,1-a]isoindole and 500 mg of an isomer 7-bromo-3-(trifluoromethyl)-5H-imidazo[2,1-a]isoindole.

[0287] MS (ESI) M / Z: 303.0 [M+H] +< .

[0288] 1< H NMR (400 MHz, DMSO-d6):δ8.15 (d, J = 0.8 Hz, 1H), 7.92 (d, J= 0.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.4, 1.8 Hz, 1H), 5.17 (s, 2H).

[0289] Step E: At room temperature, 7-bromo-2-(trifluoromethyl)-5H-imidazo[2,1-a]isoindole (930 mg, 3.08 mmol) was dissolved in methanol (35 mL). Subsequently, triethylamine (4.2 mL, 30.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (251 mg, 0.31 mmol) were added sequentially to the above solution. The reaction system was then stirred at a pressure of 40 kg of carbon monoxide gas and a temperature of 85°C for 24 hours.

[0290] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 400 mg of methyl 2-(trifluoromethyl)-5H-imidazo[2,1-a]isoindol-7-formate.

[0291] MS (ESI) M / Z: 283.1 [M+H] +< .

[0292] Step F: At 0°C, methyl 2-(trifluoromethyl)-5H-imidazo[2,1-a]isoindol-7-formate (400 mg, 1.42 mmol) was dissolved in dry tetrahydrofuran (7 mL). Subsequently, lithium aluminum hydride solution (1.13 mL, 2.84 mmol) was slowly added to the above solution dropwise. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0293] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by poured into ice water (20 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 120 mg of (2-(trifluoromethyl)-5H-imidazo[2,1-a]isoindol-7-yl)methanol.

[0294] MS (ESI) M / Z: 255.1 [M+H] +< .

[0295] Step G: At 0°C, (2-(trifluoromethyl)-5H-imidazo[2,1-a]isoindol-7-yl)methanol (120 mg, 0.47 mmol) was dissolved in dichloromethane (2.4 mL). Then, triphenylphosphine (371 mg, 1.42 mmol), sodium bicarbonate (79 mg, 0.94 mmol) and carbon tetrabromide (471 mg, 1.42 mmol) were added sequentially to the above solution. Then the reaction system was continued to be stirred at room temperature for 1 hour.

[0296] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (10 mL). The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of 7-(bromomethyl)-2-(trifluoromethyl)-5H-imidazo[2,1-a]isoindole.

[0297] MS (ESI) M / Z: 317.0 [M+H] +< .Intermediate INT-16: 9-(chloromethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine

[0298] Operation steps:

[0299] Step A: At room temperature, 3-bromo-4-formylbenzoic acid (100 g, 436.7 mmol) was dissolved in water (2.7 L). Subsequently, potassium carbonate (90.4 g, 655.1 mmol) and iodomethane (68.2 g, 480.4 mmol) were added to the above solution sequentially. Then the reaction system was continued to be stirred for 2 hours.

[0300] After the disappearance of raw materials as monitored by LCMS, the reaction solution was poured into ice water (20 mL), and a solid was precipitated and filtered. The filter cake was dried to obtain 95 g of methyl 3-bromo-4-formylbenzoate.

[0301] MS (ESI) M / Z: 243.0 [M+H] +< .

[0302] Step B: At room temperature, 3,3-dibromo-1,1,1-trifluoropropan-2-one (188.7 g, 699.3 mmol) was dissolved in water (340 mL). Subsequently, sodium acetate (57.5 g, 416.1 mmol) was added to the above solution, and the reaction system was heated to 90°C and stirred for 1 hour. Then the reaction solution was cooled down to 0°C, and methyl 3-bromo-4-formylbenzoate (85 g, 349.7 mmol) in a mixed solution of methanol / aqueous ammonia (1020 mL / 340 mL) was added dropwise. Then the reaction system was stirred at 100°C for 2 hours.

[0303] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure and filtrated. The resulting filter cake was pulped to obtain 87 g of methyl 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate.

[0304] MS (ESI) M / Z: 349.0 [M+H] +< .

[0305] Step C: At 0°C and under nitrogen protection, methyl 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (96.7 g, 277.0 mmol) was dissolved in N,N-dimethylformamide (185 mL). Subsequently, potassium carbonate (80.7 g, 583.9 mmol) and 3-bromoprop-1-ene (40.3 g, 333.1 mmol) were added to the above solution sequentially. Then the reaction system was stirred at 25°C for 20 hours.

[0306] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (800 mL). The mixture was extracted with ethyl acetate (300 mL × 3 times), and organic phases were combined and then washed with saturated saline (500 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 83.0 g of methyl 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate.

[0307] MS (ESI) M / Z: 389.0 [M+H] +< .

[0308] Step D: At 0°C and under nitrogen protection, methyl 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzoate (107 g, 275.0 mmol) was dissolved in 1,4-dioxane / water (1370 mL / 228 mL). Subsequently, potassium carbonate (76.2 g, 551.3 mmol), potassium trifluoro(vinyl)borate (96.1 g, 717.4 mmol), 2-bis(cyclohexylphosphino)-2',6'-dimethoxybiphenyl (11.3 g, 27.5 mmol), and palladium acetate (6.2 g, 27.5 mmol) were added to the above solution sequentially. Then the reaction system was stirred at 85°C for 4 hours.

[0309] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filter cake was rinsed with ethyl acetate (150 mL × 2 times). The filtrate was collected and concentrated under reduced pressure. The residue was diluted by adding water (300 mL), and the mixture was extracted with ethyl acetate (700 mL × 3 times). Organic phases were combined and then washed with saturated saline (400 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 48.4 g of methyl 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-vinylbenzoate.

[0310] MS (ESI) M / Z: 337.2 [M+H] +< .

[0311] Step E: At 0°C and under nitrogen protection, methyl 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-vinylbenzoate (61.4 g, 182.6 mmol) was dissolved in dichloromethane (730 mL). Subsequently, (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)rut henium (8.5 g, 13.7 mmol) was added to the above solution. Then the reaction system was stirred at 25°C for 3 hours.

[0312] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure and filtrated. The filter cake was rinsed with dichloromethane, and solid was collected and dried to obtain 39.0 g of methyl 2-(trifluoromethyl)-5H-benzo[c]imidazo[1,2-a]azepin-9-formate.

[0313] MS (ESI) M / Z: 309.2 [M+H] +< .

[0314] Step F: At room temperature, methyl 2-(trifluoromethyl)-5H-benzo[c]imidazo[1,2-a]azepin-9-formate (39.0 g, 125.8 mmol) and 10% palladium / carbon (8.0 g) were dissolved in methanol (132 mL). The reaction system was then stirred under hydrogen atmosphere for 18 hours.

[0315] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtrated. The filtrate was collected and concentrated under reduced pressure to obtain 37.2 g of methyl 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-formate.

[0316] MS (ESI) M / Z: 311.2 [M+H] +< .

[0317] Step G: At 0°C and under nitrogen protection, methyl 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-formate (37.2 g, 120.0 mmol) was dissolved in tetrahydrofuran (600 mL). Subsequently, 2.5 M lithium aluminum hydride solution (72 mL) was slowly added to the above solution dropwise. Then the reaction system was continued to be stirred at room temperature for 30 minutes.

[0318] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (100 mL). The reaction solution was filtered and the filter cake was rinsed with ethyl acetate (100 mL × 2 times). The filtrate was collected and layered. The aqueous phase obtained was extracted with ethyl acetate (200 mL × 3 times), and organic phases were combined and then washed with saturated saline (300 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by pulping to obtain 30 g of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methanol.

[0319] MS (ESI) M / Z: 283.3 [M+H] +< .

[0320] Step H: At 0°C and under nitrogen protection, (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methanol (30.0 g, 106.3 mmol) was dissolved in 1,2-dichloroethane (530 mL). Subsequently, thionyl chloride (37.9 g, 319 mmol) was slowly added dropwise to the above solution. Then the reaction system was stirred at 50°C for 20 minutes.

[0321] After the disappearance of raw materials as monitored by LCMS, the residue was purified by pulping to obtain 30.4 g of 9-(chloromethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine.

[0322] MS (ESI) M / Z: 301.2 [M+H] +< .Example 1: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole

[0323] Operation steps:

[0324] Step A: At room temperature, 1-bromo-2-nitrobenzene (500 mg, 2.49 mmol), (2-chloropyrimidin-5-yl)boronic acid (590 mg, 3.74 mmol), sodium carbonate (792 mg, 7.47 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (305 mg, 0.37 mmol) were dissolved in 1,4-dioxane / water (11 mL / 1.4 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 3 hours under nitrogen protection.

[0325] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (20 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (15 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 500 mg of 2-chloro-5-(2-nitrophenyl)pyrimidine.

[0326] MS (ESI) M / Z: 236.0 [M+H] +< .

[0327] Step B: At room temperature, 2-chloro-5-(2-nitrophenyl)pyrimidine (500 mg, 2.13 mmol) and 1,2-bis(diphenylphosphino)ethane (1.06 g, 2.66 mmol) were dissolved in 1,2-dichlorobenzene (7.1 mL). Then the reaction system was stirred at 160°C for 1 hour.

[0328] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (10 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 200 mg of 2-chloro-9H-pyrimido[4,5-b]indole.

[0329] MS (ESI) M / Z: 204.0 [M+H] +< .

[0330] Step C: At room temperature and under nitrogen protection, 2-chloro-9H-pyrimido[4,5-b]indole (200 mg, 0.99 mmol) was dissolved in tetrahydrofuran (5 mL). Subsequently, sodium hydride (47 mg, 1.18 mmol) was added to the above solution at 0°C and the resultant was stirred for 30 min, followed by adding 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (345 mg, 1.08 mmol). Then the reaction system was continued to be stirred at room temperature for 2 hours.

[0331] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (10 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography to obtain 300 mg of 2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole.

[0332] MS (ESI) M / Z: 442.0 [M+H] +< .

[0333] Step D: At room temperature, 2-chloro-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole (70 mg, 0.16 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (47 mg, 0.24 mmol), sodium carbonate (34 mg, 0.32 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (19 mg, 0.02 mmol) were dissolved in 1,4-dioxane / water (3.2 mL / 0.4 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C under microwave heating for 3 hours.

[0334] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and organic phases were combined and then washed with saturated saline (60 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed under reduced pressure. 15.62 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl)-9H-pyrimido[4,5-b]indole was obtained.

[0335] MS (ESI) M / Z: 556.0 [M+H] +< .

[0336] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 8.71 (s, 1H), 8.37 (d, J= 8.0 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.70 - 7.56 (m, 3H), 7.54 - 7.33 (m, 3H), 5.80 (s, 2H), 3.88 (s, 3H), 3.71 (s, 3H), 1.80 - 1.65 (m, 1H), 1.12 - 0.96 (m, 2H), 0.91 - 0.74 (m, 2H).Example 2: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo l-2-yl)benzyl)-9H-pyrimido[4,5-b]indole

[0337] Operation steps:

[0338] Step A: At room temperature and under nitrogen protection, (2-chloropyrimidin-5-yl)boronic acid (437 mg, 2.81 mmol) was dissolved in dry 1,4-dioxane / water (8.4 mL / 0.93 mL). Subsequently, 1-bromo-2-nitrobenzene (378 mg, 1.87 mmol), sodium carbonate (595 mg, 5.61 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (230 mg, 0.28 mmol) were added sequentially to the above solution. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then heated to 90°C and stirred for 16 hour.

[0339] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (50 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 280 mg of 2-chloro-5-(2-nitrophenyl)pyrimidine.

[0340] MS (ESI) M / Z: 236.0 [M+H] +< .

[0341] Step B: At room temperature, 2-chloro-5-(2-nitrophenyl)pyrimidine (280 mg, 1.19 mmol) was dissolved in 1,2-dichlorobenzene (4 mL). Subsequently, 1,2-bis(diphenylphosphino)ethane (593 mg, 1.49 mmol) was added to the above solution. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then heated to 160°C and stirred for 2 hours.

[0342] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 120 mg of 2-chloro-9H-pyrimido[4,5-b]indole.

[0343] MS (ESI) M / Z: 204.0 [M+H] +< .

[0344] Step C: At room temperature and under nitrogen protection, 2-chloro-9H-pyrimido[4,5-b]indole (120 mg, 0.59 mmol) was dissolved in dry tetrahydrofuran (2 mL). Subsequently, sodium hydride (29 mg, 0.71 mmol) was added to the above solution at 0°C, and the resultant was stirred for 30 minutes. Then 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (160 mg, 0.65 mmol) was added, and the mixture was heated to room temperature and stirred for 2 hours.

[0345] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the resulting residue was quenched by adding ice water (30 mL), and the mixture was extracted with ethyl acetate (10 mL × 3 times). Organic phases were combined and then washed with saturated saline (15 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 60 mg of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indol e.

[0346] MS (ESI) M / Z: 470.0 [M+H] +< .

[0347] Step D: At room temperature and under nitrogen protection, 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indol e (60 mg, 0.13 mmol) was dissolved in dry 1,4-dioxane / water (0.9 mL / 0.1 mL). Subsequently, (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (50 mg, 0.27 mmol), cesium carbonate (83 mg, 0.27 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (20 mg, 0.03 mmol) were added successively. The reaction system was evacuated to remove air and purged with nitrogen for 3 times and then heated to 90°C by microwave heating and stirred for 3 hours.

[0348] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed under reduced pressure. 7.66 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole was obtained.

[0349] MS (ESI) M / Z: 583.8 [M+H] +< .

[0350] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.66 (s, 1H), 8.70 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.54 - 7.38 (m, 5H), 5.81 (s, 2H), 4.44 - 4.30 (m, 1H), 3.87 (s, 3H), 1.75 - 1.69 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H), 1.10 - 1.01 (m, 2H), 0.88 - 0.79 (m, 2H).Example 3: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo l-2-yl)benzyl)-9H-pyridino[2',3':4,5]pyrrolo[2,3-d]pyrimidine

[0351] Operation steps:

[0352] Step A: At room temperature, (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.33 mmol), 2-bromo-3-nitropyridine (857 mg, 4.2 mmol) and sodium carbonate (1.34 g, 12.64 mmol) were dissolved in 1,4-dioxane / water (21 mL / 2.3 mL). Subsequently, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (513 mg, 0.6 mmol) was added to the above solution, and the reaction system was evacuated to remove air and purged with nitrogen for 4 times, and then heated to 100°C and stirred for 16 hours.

[0353] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (15 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 600 mg of 2-chloro-5-(3-nitropyridin-2-yl)pyrimidine.

[0354] MS (ESI) M / Z: 237.0 [M+H] +< .

[0355] Step B: At room temperature, 2-chloro-5-(3-nitropyridin-2-yl)pyrimidine (600 mg, 2.54 mmol) and 1,2-bis(diphenylphosphino)ethane (1.26 g, 3.18 mmol) were dissolved in 1,2-dichlorobenzene (13 mL). The reaction system was evacuated to remove air and purged with nitrogen for 4 times, and then heated to 160°C and stirred for 2 hours.

[0356] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (15 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 400 mg of 2-chloro-9H-pyridino[2',3':4,5]pyrrolo[2,3-d]pyrimidine.

[0357] MS (ESI) M / Z: 205.2 [M+H] +< .

[0358] Step C: At room temperature and under nitrogen protection, 2-chloro-9H-pyridino[2',3':4,5]pyrrolo[2,3-d]pyrimidine (400 mg, 1.96 mmol), (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (555 mg, 1.96 mmol) and triphenylphosphine (771 mg, 2.94 mmol) were dissolved in dry tetrahydrofuran (10 mL). Subsequently, diisopropyl azodicarboxylate (594 mg, 2.94 mmol) was slowly added dropwise to the above solution at 0°C. Then the reaction system was continued to be stirred at room temperature for 2 hours.

[0359] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (15 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 250 mg of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyridino[2',3':4,5]py rrolo[2,3-d]pyrimidine.

[0360] MS (ESI) M / Z: 470.8 [M+H] +< .

[0361] Step D: At room temperature, 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyridino[2',3':4,5]py rrolo[2,3-d]pyrimidine (250 mg, 0.53 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (210 mg, 1.07 mmol), and cesium carbonate (346 mg, 1.06 mmol) were dissolved in 1,4-dioxane / water (3 mL / 0.3 mL). Subsequently, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (85 mg, 0.11 mmol) was added to the above solution. The reaction system was evacuated to remove air and purged with nitrogen for 4 times, and then stirred at 100°C under microwave heating for 3 hours.

[0362] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed under reduced pressure. 7.35 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyridino[2',3':4,5]pyrrolo[2,3-d]pyrimidine was obtained.

[0363] MS (ESI) M / Z: 585.0 [M+H] +< .

[0364] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.70 (s, 1H), 8.72 (s, 1H), 8.70 (dd, J = 4.8, 1.2 Hz, 1H), 8.37 (dd, J = 8.4, 1.2 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.66 (dd, J = 8.4, 4.8 Hz, 1H), 7.50 (brs, 4H), 5.85 (s, 2H), 4.45 - 4.32 (m, 1H), 3.88 (s, 3H), 1.80 - 1.70 (m, 1H), 1.35 (d, J= 6.4 Hz, 6H), 1.11 - 1.03 (m, 2H), 0.89 - 0.79 (m, 2H).Example 4: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H -imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole

[0365] Operation steps:

[0366] Step A: At room temperature, 2-bromo-1-fluoro-3-nitrobenzene (914 mg, 4.15 mmol), (2-chloropyrimidin-5-yl)boronic acid (985 mg, 6.23 mmol), sodium carbonate (1.32 g, 12.45 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (508 mg, 0.62 mmol) were dissolved in 1,4-dioxane / water (20.7 mL / 2.3 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 3 hours.

[0367] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (40 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and organic phases were combined and then washed with saturated saline (60 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 516 mg of 2-chloro-5-(2-fluoro-6-nitrophenyl)pyrimidine.

[0368] MS (ESI) M / Z: 254.0 [M+H] +< .

[0369] Step B: At room temperature, 2-chloro-5-(2-fluoro-6-nitrophenyl)pyrimidine (400 mg, 1.58 mmol) and 1,2-bis(diphenylphosphino)ethane (786 mg, 1.97 mmol) were dissolved in 1,2-dichlorobenzene (7.9 mL). Then the reaction system was stirred at 160°C for 1 hour.

[0370] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 276 mg of 2-chloro-5-fluoro-9H-pyrimido[4,5-b]indole.

[0371] MS (ESI) M / Z: 222.0 [M+H] +< .

[0372] Step C: At room temperature and under nitrogen protection, 2-chloro-5-fluoro-9H-pyrimido[4,5-b] indole (226 mg, 1.02 mmol) and 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (283 mg, 0.82 mmol) were dissolved in N,N-dimethylformamide (5 mL). Subsequently, potassium carbonate (281 mg, 2.04 mmol) was added to the above solution. Then the reaction system was stirred at 50°C for 2 hours.

[0373] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (40 mL), and the mixture was extracted with ethyl acetate (15 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 220 mg of 2-chloro-5-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4, 5-b]indole.

[0374] MS (ESI) M / Z: 488.0 [M+H] +< .

[0375] Step D: At room temperature, 2-chloro-5-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4, 5-b]indole (200 mg, 0.41 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (239 mg, 1.23 mmol), cesium carbonate (200 mg, 0.62 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (65 mg, 0.08 mmol) were dissolved in 1,4-dioxane / water (2 mL / 0.2 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 100°C under microwave heating for 3 hours.

[0376] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL), and the mixture was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (60 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed under reduced pressure. 16.09 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-im idazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole was obtained.

[0377] MS (ESI) M / Z: 602.4 [M+H] +< .

[0378] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.52 (s, 1H), 8.71 (s, 1H), 8.15 (d, J= 1.2 Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.52 - 7.47 (m, 4H), 7.31 - 7.26 (m, 1H), 5.83 (s, 2H), 4.44 - 4.33 (m, 1H), 3.88 (s, 3H), 1.78 - 1.69 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H), 1.10 - 1.02 (m, 2H), 0.88 - 0.80 (m, 2H).Example 5: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H -imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole

[0379] Operation steps:

[0380] Step A: At room temperature, 1-bromo-4-fluoro-2-nitrobenzene (1.50 g, 6.85 mmol), (2-chloropyrimidin-5-yl)boronic acid (1.62 g, 10.27 mmol), sodium carbonate (2.18 g, 20.55 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (840 mg, 1.03 mmol) were dissolved in 1,4-dioxane / water (31 mL / 3.5 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 3 hour.

[0381] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (60 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of 2-chloro-5-(4-fluoro-2-nitrophenyl)pyrimidine.

[0382] MS (ESI) M / Z: 253.8 [M+H] +< .

[0383] Step B: At room temperature, 2-chloro-5-(4-fluoro-2-nitrophenyl)pyrimidine (1.1 g, 4.34 mmol) and 1,2-bis(diphenylphosphino)ethane (2.16 g, 5.43 mmol) were dissolved in 1,2-dichlorobenzene (15 mL). Then the reaction system was stirred at 160°C for 2 hours.

[0384] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (50 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 261 mg of 2-chloro-7-fluoro-9H-pyrimido[4,5-b]indole.

[0385] MS (ESI) M / Z: 221.9 [M+H] +< .

[0386] Step C: At room temperature and under nitrogen protection, 2-chloro-7-fluoro-9H-pyrimido[4,5-b] indole (261 mg, 1.18 mmol), 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (490 mg, 1.42 mmol), and potassium carbonate (326 mg, 2.36 mmol) were dissolved in N,N-dimethylformamide (6 mL). Then the reaction system was stirred at 50°C for 2 hours.

[0387] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (30 mL), and the mixture was extracted with ethyl acetate (10 mL × 3 times). Organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 170 mg of 2-chloro-7-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4, 5-b]indole.

[0388] MS (ESI) M / Z: 487.8 [M+H] +< .

[0389] Step D: At room temperature, 2-chloro-7-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4, 5-b]indole (130 mg, 0.27 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (156 mg, 0.80 mmol), cesium carbonate (174 mg, 0.53 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (42 mg, 0.05 mmol) were dissolved in 1,4-dioxane / water (1.2 mL / 0.13 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C under microwave heating for 3 hours.

[0390] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed under reduced pressure. 17.11 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-im idazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole was obtained.

[0391] MS (ESI) M / Z: 602.0 [M+H] +< .

[0392] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 8.70 (s, 1H), 8.41 (dd, J = 8.6, 5.4 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.85 (dd, J = 10.0, 2.4 Hz, 1H), 7.54 - 7.46 (m, 4H), 7.33 - 7.26 (m, 1H), 5.79 (s, 2H), 4.45 - 4.31 (m, 1H), 3.87 (s, 3H), 1.75 - 1.66 (m, 1H), 1.35 (d, J= 6.8 Hz, 6H), 1.09 - 1.00 (m, 2H), 0.88 - 0.77 (m, 2H).Example 6: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H -imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole

[0393] Operation steps:

[0394] Step A: At room temperature, 1-bromo-3-fluoro-2-nitrobenzene (1 g, 4.54 mmol), (2-chloropyrimidin-5-yl)boronic acid (1.79 g, 6.82 mmol), sodium carbonate (1.45 g, 13.63 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (498 mg, 0.68 mmol) were dissolved in 1,4-dioxane / water (19.8 mL / 2.2 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 3 hours.

[0395] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (20 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (15 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 500 mg of 2-chloro-5-(3-fluoro-2-nitrophenyl)pyrimidine.

[0396] MS (ESI) M / Z: 254.0 [M+H] +< .

[0397] Step B: At room temperature, 2-chloro-5-(3-fluoro-2-nitrophenyl)pyrimidine (500 mg, 1.97 mmol) and 1,2-bis(diphenylphosphino)ethane (979 mg, 2.46 mmol) were dissolved in 1,2-dichlorobenzene (7.1 mL). Then the reaction system was stirred at 160°C for 1 hour.

[0398] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (10 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 60 mg of 2-chloro-8-fluoro-9H-pyrimido[4,5-b]indole.

[0399] MS (ESI) M / Z: 222.0 [M+H] +< .

[0400] Step C: At room temperature and under nitrogen protection, 2-chloro-8-fluoro-9H-pyrimido[4,5-b]indole (60 mg, 0.27 mmol) and anhydrous potassium carbonate (75 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (3 mL). Then 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (113 mg, 0.31 mmol) was added to the above solution. Then the reaction system was stirred at room temperature for 2 hours.

[0401] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (10 mL), and the mixture was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 90 mg of 2-chloro-8-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4, 5-b]indole.

[0402] MS (ESI) M / Z: 488.3 [M+H] +< .

[0403] Step D: At room temperature, 2-chloro-8-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4, 5-b]indole (90 mg, 0.184 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (107.8 mg, 0.55 mmol), cesium carbonate (120 mg, 0.37 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (22 mg, 0.03 mmol) were dissolved in 1,4-dioxane / water (0.8 mL / 0.08 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C under microwave heating for 2.5 hours.

[0404] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL), and the mixture was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (60 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed under reduced pressure. 4.89 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-fluoro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-im idazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole was obtained.

[0405] MS (ESI) M / Z: 602.2 [M+H] +< .

[0406] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.75 (s, 1H), 8.71 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.55 - 7.46 (m, 3H), 7.45 - 7.35 (m, 3H), 5.86 (s, 2H), 4.45 - 4.32 (m, 1H), 3.87 (s, 3H), 1.77 - 1.68 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H), 1.09 - 1.02 (m, 2H), 0.88 - 0.81 (m, 2H).Example 7: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo l-2-yl)benzyl)-7-methoxy-9H-pyrimido[4,5-b]indole

[0407] Operation steps:

[0408] Step A: At room temperature, (2-chloropyrimidin-5-yl)boronic acid (1.5 g, 9.49 mmol), 1-bromo-4-methoxy-2-nitrobenzene (1.5 g, 6.49 mmol) and sodium carbonate (2.1 g, 19.81 mmol) were dissolved in 1,4-dioxane / water (32 mL / 3.5 mL). Subsequently, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (0.8 g, 0.98 mmol) was added to the above solution, and the reaction system was evacuated to remove air and purged with nitrogen for 4 times, and then stirred at 100°C for 16 hours.

[0409] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (15 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 740 mg of 2-chloro-5-(4-methoxy-2-nitrophenyl)pyrimidine.

[0410] MS (ESI) M / Z: 266.0 [M+H] +< .

[0411] Step B: At room temperature, 2-chloro-5-(4-methoxy-2-nitrophenyl)pyrimidine (740 mg, 2.79 mmol) and 1,2-bis(diphenylphosphino)ethane (2.22 g, 5.58 mmol) were dissolved in 1,2-dichlorobenzene (14 mL). The reaction system was evacuated to remove air and purged with nitrogen for 4 times, and then stirred at 160°C for 2 hours.

[0412] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (15 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 440 mg of 2-chloro-7-methoxy-9H-pyrimido[4,5-b]indole.

[0413] MS (ESI) M / Z: 234.0 [M+H] +< .

[0414] Step C: At room temperature and under nitrogen protection, 2-chloro-7-methoxy-9H-pyrimido[4,5-b]indole (440 mg, 1.89 mmol), 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (410 mg, 1.13 mmol), and potassium carbonate (521 mg, 3.78 mmol) were dissolved in dry N,N-dimethylformamide (10 mL). The reaction system was stirred at 50°C for 2 hours.

[0415] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (50 mL), and the mixture was extracted with ethyl acetate (150 mL × 3 times). Organic phases were combined and then washed with saturated saline (25 mL). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 70 mg of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-methoxy-9H-pyrimido [4,5-b]indole.

[0416] MS (ESI) M / Z: 500.0 [M+H] +< .

[0417] Step D: At room temperature, 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-methoxy-9H-pyrimido [4,5-b]indole (70 mg, 0.14 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (84 mg, 0.43 mmol), and cesium carbonate (70 mg, 0.21 mmol) were dissolved in 1,4-dioxane / water (1 mL / 0.1 mL). Subsequently, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (22 mg, 0.03 mmol) was added to the above solution. The reaction system was evacuated to remove air and purged with nitrogen for 4 times, and then stirred at 90°C under microwave heating for 3 hours.

[0418] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed under reduced pressure. 9.8 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-methoxy-9H-pyrimido[4,5-b]indole was obtained.

[0419] MS (ESI) M / Z: 614.0 [M+H] +< .

[0420] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.51 (s, 1H), 8.69 (s, 1H), 8.24 (d, J= 8.4 Hz, 1H), 8.14 (s, 1H), 7.49 (brs, 4H), 7.43 (d, J = 2.0 Hz, 1H), 7.04 (dd, J =8.8, 2.4 Hz, 1H), 5.78 (s, 2H), 4.45 - 4.32 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 1.74 - 1.66 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H), 1.07 - 1.00 (m, 2H), 0.85 - 0.78 (m, 2H).Example 8: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo l-2-yl)benzyl)-7-(trifluoroethyl)-9H-pyrimido[4,5-b]indole

[0421] Operation steps:

[0422] Step A: At room temperature, 1-bromo-2-nitro-4-(trifluoromethyl)benzene (1 g, 3.70 mmol), (2-chloropyrimidin-5-yl)boronic acid (879 mg, 5.60 mmol), sodium carbonate (1.2 g, 11.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (406 mg, 0.56 mmol) were dissolved in 1,4-dioxane / water (18 mL / 2 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 16 hours.

[0423] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (20 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (15 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 620 mg of 2-chloro-5-(4-trifluoromethyl-2-nitrophenyl)pyrimidine.

[0424] MS (ESI) M / Z: 304.0 [M+H] +< .

[0425] Step B: At room temperature, 2-chloro-5-(4-trifluoromethyl-2-nitrophenyl)pyrimidine (620 mg, 2.04 mmol) and 1,2-bis(diphenylphosphino)ethane (1.1 g, 2.55 mmol) were dissolved in 1,2-dichlorobenzene (9.5 mL). Then the reaction system was stirred at 160°C for 2 hours.

[0426] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL), and the mixture was extracted with ethyl acetate (20 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 220 mg of 2-chloro-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indole.

[0427] MS (ESI) M / Z: 272.0 [M+H] +< .

[0428] Step C: At room temperature and under nitrogen protection, 2-chloro-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indole (220 mg, 0.81 mmol) and anhydrous potassium carbonate (223.6 mg, 1.62 mmol) were dissolved in N,N-dimethylformamide (5 mL). Then 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (337 mg, 0.97 mmol) was added to the above solution. Then the reaction system was stirred at 55°C for 2 hours.

[0429] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (10 mL), and the mixture was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 450 mg of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(trifluoroethyl)-9H-pyr imido[4,5-b]indole.

[0430] MS (ESI) M / Z: 538.0 [M+H] +< .

[0431] Step D: At room temperature, 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(trifluoroethyl)-9H-pyr imido[4,5-b]indole (270 mg, 0.50 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (294 mg, 1.51 mmol), cesium carbonate (327 mg, 1.0 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (60 mg, 0.075 mmol) were dissolved in 1,4-dioxane / water (2.5 mL / 0.25 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C under microwave heating for 2.5 hours.

[0432] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and organic phases were combined and then washed with saturated saline (60 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed. 27.13 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(trifluoroethyl)-9H-pyrimido[4,5-b]indole was obtained.

[0433] MS (ESI) M / Z: 652.0 [M+H] +< .

[0434] 1< H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 8.72 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.52 - 7.46 (m, 4H), 5.93 (s, 2H), 4.42 - 4.32 (m, 1H), 3.87 (s, 3H), 1.76 - 1.68 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H), 1.09 - 1.03 (m, 2H), 0.86 - 0.79 (m, 2H).Example 9: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole

[0435]

[0436] Step A: At room temperature and under nitrogen protection, 2-(4-(bromomethyl)phenyl)-1-ethyl-4-(trifluoromethyl)-1H-imidazole (200 mg, 0.60 mmol), 2-chloro-9H-pyrimido[4,5-b]indole (245 mg, 1.20 mmol) and potassium carbonate (182 mg, 1.20 mmol) were dissolved in N,N-dimethylformamide (4 mL). Then the reaction system was heated to 50°C and stirred for 2 hours.

[0437] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (30 mL). The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 130 mg of 2-chloro-9-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole.

[0438] MS (ESI) M / Z: 455.8 [M+H] +< .

[0439] Step B: At room temperature, 2-chloro-9-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyrimido[4,5-b]indole (110 mg, 0.24 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (94 mg, 0.48 mmol), cesium carbonate (158 mg, 0.48 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (38 mg, 0.05 mmol) were dissolved in 1,4-dioxane / water (1.1 mL / 0.12 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C under microwave heating for 3 hours.

[0440] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (30 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed. 55.00 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)b enzyl)-9H-pyrimido[4,5-b]indole was obtained.

[0441] MS (ESI) M / Z: 570.1 [M+H] +< .

[0442] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.66 (s, 1H), 8.71 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 8.0 Hz, 1H), 5.80 (s, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.77 - 1.68 (m, 1H) ,1.26 (t, J = 7.2 Hz, 3H), 1.10 - 1.02 (m, 2H), 0.89 - 0.80 (m, 2H).Example 10: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-pyrimido[4,5-b]indole

[0443] Operation steps:

[0444] Step A: At room temperature, 4-hydrazinylbenzoic acid (5 g, 32.9 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (6 g, 32.9 mmol) were dissolved in methanol / hydrochloric acid (73 mL / 14.6 mL). Then the reaction system was stirred at room temperature for 3 hours.

[0445] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 8.3 g of methyl 4-(5-hydroxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate.

[0446] MS (ESI) M / Z: 287.0 [M+H] +< .

[0447] Step B: At room temperature and under nitrogen protection, methyl 4-(5-hydroxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (5 g, 17.5 mmol) was dissolved in N,N-dimethylformamide (87 mL). Subsequently, sodium hydride (1.39 g, 34.96 mmol) was added to the above solution, and the resultant was stirred for 30 minutes. Then iodoethane (5.4 g, 34.96 mmol) was slowly added dropwise, and the reaction system was stirred at room temperature for 1 hour.

[0448] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (250 mL). The mixed solution was extracted with ethyl acetate (80 mL × 3 times), and organic phases were combined and then washed with saturated saline (250 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.7 g of methyl 4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate.

[0449] MS (ESI) M / Z: 315.0 [M+H] +< .

[0450] Step C: At 0°C and under nitrogen protection, methyl 4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (3.7 g, 11.78 mmol) was dissolved in tetrahydrofuran (59 mL). Subsequently, lithium aluminum hydride (9.4 mL, 23.56 mmol) was added to the above solution, and the reaction system was continued to be stirred for 30 minutes.

[0451] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by slowly adding to ice water (150 mL) dropwise, and the mixture was filtrated. Then the filtrate was extracted with ethyl acetate (50 mL × 3 times). Organic phases were combined and then washed with saturated saline (150 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3 g of (4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol.

[0452] MS (ESI) M / Z: 287.0 [M+H] +< .

[0453] Step D: At 0°C and under nitrogen protection, (4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (1.5 g, 5.24 mmol) was dissolved in dichloromethane (26 mL). Then, triphenylphosphine (2.7 g, 10.48 mmol), sodium bicarbonate (880 mg, 10.48 mmol) and carbon tetrabromide (3.46 g, 10.48 mmol) were added sequentially to the above solution. Then the reaction system was continued to be stirred at room temperature for 30 minutes.

[0454] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (150 mL). The mixed solution was extracted with dichloromethane (50 mL × 3 times), and organic phases were combined and then washed with saturated saline (150 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.8 g of 1-(4-(bromomethyl)phenyl)-5-ethoxy-3-(trifluoromethyl)-1H-pyrazole.

[0455] MS (ESI) M / Z: 348.8 [M+H] +< .

[0456] Step E: At room temperature, 1-(4-(bromomethyl)phenyl)-5-ethoxy-3-(trifluoromethyl)-1H-pyrazole (43.9 mg, 0.13 mmol), 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyrimido[4,5-b]indole (40 mg, 0.13 mmol) and potassium carbonate (34.7 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 50°C for 2 hours.

[0457] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding water (40 mL). The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and organic phases were combined and then washed with saturated saline (25 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed. 17.29 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)b enzyl)-9H-pyrimido[4,5-b]indole was obtained.

[0458] MS (ESI) M / Z: 586.2 [M+H] +< .

[0459] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 8.70 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.65 - 7.58 (m, 3H), 7.49 - 7.42 (m, 3H), 6.42 (s, 1H), 5.78 (s, 2H), 4.25 (q, J = 6.8 Hz, 2H), 3.87 (s, 3H), 1.77 - 1.65 (m, 1H), 1.30 (t, J = 6.8 Hz, 3H), 1.10 - 1.00 (m, 2H), 0.89 - 0.76 (m, 2H).Example 11: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo l-2-yl)benzyl)-4-methyl-9H-pyrimido[4,5-b]indole

[0460] Operation steps:

[0461] Step A: At room temperature, (2-nitrophenyl)boronic acid (1.03 g, 6.15 mmol), 5-bromo-2-chloro-4-methylpyrimidine (850 mg, 4.10 mmol), sodium carbonate (1.3 g, 12.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (450 mg, 0.61 mmol) were dissolved in 1,4-dioxane / water (21 mL / 2.3 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 16 hours.

[0462] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (40 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (15 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 600 mg of 2-chloro-4-methyl-5-(2-nitrophenyl)pyrimidine.

[0463] MS (ESI) M / Z: 250.0 [M+H] +< .

[0464] Step B: At room temperature, 2-chloro-4-methyl-5-(2-nitrophenyl)pyrimidine (600 mg, 2.41 mmol) and 1,2-bis(diphenylphosphino)ethane (1198.8 mg, 3.01 mmol) were dissolved in 1,2-dichlorobenzene (12 mL). Then the reaction system was stirred at 160°C for 2 hours.

[0465] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (40 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 320 mg of 2-chloro-4-methyl-9H-pyrimido[4,5-b]indole.

[0466] MS (ESI) M / Z: 218.0 [M+H] +< .

[0467] Step C: At room temperature and under nitrogen protection, 2-chloro-4-methyl-9H-pyrimido[4,5-b]indole (150 mg, 0.69 mmol) and anhydrous potassium carbonate (190.2 mg, 1.38 mmol) were dissolved in N,N-dimethylformamide (5 mL). Then 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (286.7 mg, 0.83 mmol) was added to the above solution. Then the reaction system was stirred at 55°C for 2 hours.

[0468] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL). The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 220 mg of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-methyl-9H-pyrimido[4 ,5-b]indole.

[0469] MS (ESI) M / Z: 484.0 [M+H] +< .

[0470] Step D: At room temperature, 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-methyl-9H-pyrimido[4 ,5-b]indole (180 mg, 0.37 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (145 mg, 0.75 mmol), cesium carbonate (243 mg, 0.75 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (59 mg, 0.08 mmol) were dissolved in 1,4-dioxane / water (1.7 mL / 0.20 mL). The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C under microwave heating for 2.5 hours.

[0471] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (30 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected and solvent was removed. 88.80 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-methyl-9H-pyrimido[4,5-b]indole was obtained.

[0472] MS (ESI) M / Z: 598.2 [M+H] +< .

[0473] 1< H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.52 - 7.41 (m, 5H), 5.81 (s, 2H), 4.43 - 4.30 (m, 1H), 3.87 (s, 3H), 3.03 (s, 3H), 1.74 - 1.63 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H), 1.09 - 1.00 (m, 2H), 0.90 - 0.77 (m, 2H).Example 12: (S)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-i midazol-2-yl)benzyl)ethyl)-9H-pyrimido[4,5-b]indole and (R)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-i midazol-2-yl)benzyl)ethyl)-9H-pyrimido[4,5-b]indole

[0474]

[0475] The compounds were prepared with reference to the preparation method of Example 8 and obtained by chiral splitting (chiral conditions were omitted in the synthesis report). The products were separated by chiral supercritical fluid chromatography (SFC) under the following conditions: chiral column Daicel IG-3 (25×250 mm, 10 µm); mobile phase: carbon dioxide / methanol [0.2% ammonia (7 M ammonia in methanol)], and 27.65 mg of compound 13-P1 (peak time: 1.77 min) and 32.27 mg of compound 13-P2 (peak time: 3.27 min) were obtained.Compound 13-P1:

[0476] MS (ESI) M / Z: 598.1 [M+H] +< .

[0477] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 8.70 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.60 - 7.47 (m, 5H), 7.41 (t, J = 7.4 Hz, 1H), 6.55 (q, J = 7.2 Hz, 1H), 4.47 - 4.31 (m, 1H), 3.87 (s, 3H), 2.15 (d, J= 7.2 Hz, 3H), 1.82 - 1.67 (m, 1H), 1.36 (dd, J = 6.6, 1.8 Hz, 6H), 1.11 - 1.01 (m, 2H), 0.90 - 0.77 (m, 2H).Compound 13-P2:

[0478] MS (ESI) M / Z: 598.2 [M+H] +< .

[0479] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 8.70 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.58-7.48 (m, 5H), 7.41 (t, J = 7.6 Hz, 1H), 6.55 (q, J = 7.2 Hz, 1H), 4.46 - 4.35 (m, 1H), 3.87 (s, 3H), 2.15 (d, J = 7.2 Hz, 3H), 1.80 - 1.69 (m, 1H), 1.36 (dd, J = 6.6, 1.7 Hz, 6H), 1.09 - 1.01 (m, 2H), 0.92 - 0.79 (m, 2H).Example 13: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo l-2-yl)benzyl)-9H-imidazo[2,1-f]purine

[0480] Operation steps:

[0481] Step A: At 0°C, (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methylamine (2.25 g, 7.96 mmol) and ethyl 2,4-dichloropyrimidin-5-carboxylate (1.76 g, 7.96 mmol) were dissolved in acetonitrile (40 mL). Subsequently, N,N-diisopropylethylamine (267 mg, 2.07 mmol) was slowly added to the above solution dropwise. Then the reaction system was continued to be stirred for 1 hour.

[0482] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding to ice water (100 mL). The mixed solution was extracted with ethyl acetate (40 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.4 g of ethyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-carb oxylate.

[0483] MS (ESI) M / Z: 468.0 [M+H] +< .

[0484] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.05 (t, J = 6.2 Hz, 1H), 8.67 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 4.53 - 4.42 (m, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.40 (d, J = 6.8 Hz, 6H), 1.33 (t, J = 7.2 Hz, 3H).

[0485] Step B: At 0°C, ethyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-carb oxylate (2.4 g, 4.9 mmol) and lithium hydroxide (413 mg, 9.8 mmol) were dissolved in tetrahydrofuran / water (12.5 mL / 12.5 mL). Then the reaction system was stirred at room temperature for 2 hours.

[0486] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the resulting residue was quenched by adding to ice water (30 mL). The mixture was adjusted to pH 3-4 with 3 M dilute hydrochloric acid at 0°C and filtered. The filter cake was rinsed with water (20 mL × 3 times), and then collected and concentrated under reduced pressure to obtain 2.2 g of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-carb oxylic acid.

[0487] MS (ESI) M / Z: 440.0 [M+H] +< .

[0488] Step C: At room temperature, 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-carb oxylic acid (2.2 g, 5.01 mmol), diphenyl azidophosphate (1.38 g, 5.01 mmol) and triethylamine (506 mg, 5.01 mmol) were dissolved in N,N-dimethylformamide (25 mL). Then the reaction system was stirred at 115°C for 16 hours.

[0489] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.4 g of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one.

[0490] MS (ESI) M / Z: 437.0 [M+H] +< .

[0491] Step D: At 0°C and under nitrogen protection, 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one (2.2 g, 5.05 mmol) and triethylamine (1 g, 10.09 mmol) were dissolved in phosphorus oxychloride (25 mL). Then the reaction system was stirred at 140°C for 24 hours.

[0492] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was quenched by adding ice water (100 mL). The mixed solution was extracted with ethyl acetate (40 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 70 mg of 2,8-dichloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine.

[0493] MS (ESI) M / Z: 455.0 [M+H] +< .

[0494] Step E: At room temperature and under nitrogen protection, 2,8-dichloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine (70 mg, 0.15 mmol) was dissolved in ammonia in methanol (2 mL, 7 M). Then the reaction system was stirred at 80°C for 2 hours.

[0495] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purin-8-amine.

[0496] MS (ESI) M / Z: 436.0 [M+H] +< .

[0497] Step F: At room temperature and under nitrogen protection, 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purin-8-amine (25 mg, 0.06 mmol) and 2-chloroacetaldehyde (71 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (2 mL). Then the reaction system was stirred at 100°C for 18 hours.

[0498] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (50 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 8 mg of 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[2,1-f]purine

[0499] MS (ESI) M / Z: 460.0 [M+H] +< .

[0500] Step G: At room temperature, 2-chloro-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[2,1-f]purine (8 mg, 0.02 mmol) was dissolved in 1,4-dioxane / water (0.5 mL / 0.05 mL). Subsequently, (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (8 mg, 0.04 mmol), cesium carbonate (7 mg, 0.02 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (3 mg, 0.004 mmol) were added successively to the above reaction solution. The reaction system was evacuated to remove air and purged with nitrogen for 4 times, and then stirred at 90°C under microwave heating for 2 hours.

[0501] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding ice water (50 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and organic phases were combined and then washed with saturated saline (20 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-imidazo[2,1-f]purine.

[0502] MS (ESI) M / Z: 574.2 [M+H] +< .

[0503] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.24 (s, 1H), 8.70 (s, 1H), 8.16 (d, J= 1.4 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 1.6 Hz, 1H), 5.52 (s, 2H), 4.48 - 4.35 (m, 1H), 3.86 (s, 3H), 1.79 - 1.67 (m, 1H), 1.37 (d, J = 6.6 Hz, 7H), 1.10 - 1.01 (m, 2H), 0.89 - 0.79 (m, 2H).Example 14: 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo l-2-yl)benzyl)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine

[0504] Operation steps:

[0505] Step A: 4-Methoxybenzaldehyde (13 g, 95.59 mmol) and triethylamine (21 g, 210.3 mmol) were dissolved in dichloromethane (200 mL) at room temperature. Subsequently, the reaction solution was cooled to 0°C, and methyl glycinate (17 g, 191.2 mmol) and anhydrous sodium sulfate (50 g, 352.1 mmol) were added to the above reaction solution. The reaction system was then stirred at room temperature for 16 hours.

[0506] After the disappearance of raw materials as monitored by LCMS, the solution was filtered and concentrated under reduced pressure. 20 g of methyl 2-((4-methoxybenzylidene)amino)acetate was obtained.

[0507] MS (ESI) M / Z: 208.1 [M+H] +< .

[0508] Step B: Methyl 2-((4-methoxybenzylidene)amino)acetate (18 g, 86.96 mmol) was dissolved in methanol (200 mL) at 0°C. Subsequently, sodium borohydride (4.96 g, 130.44 mmol) was slowly added. Then the reaction system was stirred at room temperature for 2 hours.

[0509] After the disappearance of raw materials as monitored by LCMS, ice water (500 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined and washed with saturated saline (100 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 15 g of methyl (4-methoxybenzyl)glycinate.

[0510] MS (ESI) M / Z: 210.1 [M+H] +< .

[0511] Step C: Methyl (4-methoxybenzyl)glycinate (15 g, 71.77 mmol), 4-chloro-2-(methylthio)pyrimidin-5-formaldehyde (13.4 g, 71.77 mmol) and triethylamine (8.7 g, 86.12 mmol) were dissolved in tetrahydrofuran (360 mL) at room temperature. The reaction system was then stirred at room temperature for 16 hours.

[0512] After the disappearance of raw materials as monitored by LCMS, ice water (300 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated saline (50 mL × 2 times). Then the resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 22 g of methyl N-(5-formyl-2-(methylthio)pyrimidin-4-yl)-N-(4-methoxybenzyl)glycinate.

[0513] MS (ESI) M / Z: 362.0 [M+H] +< .

[0514] Step D: Methyl N-(5-formyl-2-(methylthio)pyrimidin-4-yl)-N-(4-methoxybenzyl)glycinate (16.5 g, 45.71 mmol) was dissolved in dry toluene (160 mL) under nitrogen protection at room temperature. Subsequently, sodium hydride (7.31 g, 182.83 mmol) was slowly added to the above solution under the condition of ice-water bath. The reaction system was then stirred at 70°C for 2 hours.

[0515] After the disappearance of raw materials as monitored by LCMS, ice water (500 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated saline (100 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 10 g of methyl 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxylate.

[0516] MS (ESI) M / Z: 344.0 [M+H] +< .

[0517] Step E: Methyl 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxylate (10 g, 29.15 mmol) was dissolved in dry dichloromethane (147 mL) at room temperature. Subsequently, at -78°C, lithium aluminum hydride (1 moL / L) (59.30 ml, 59.30 mmol) was added to the above reaction solution. Then the reaction system reacted at -78°C for 30 minutes.

[0518] After the disappearance of raw materials as monitored by LCMS, the reaction solution was added to ice water (500 mL) for quenching. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated saline (100 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 10 g of (7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol.

[0519] MS (ESI) M / Z: 316.0 [M+H] +< .

[0520] Step F: (7-(4-Methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (10 g, 31.75 mmol) and manganese dioxide (13.65 g, 158.75 mmol) were dissolved in dichloromethane (635 mL) at room temperature. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and the reaction system was stirred at room temperature for 2 hours.

[0521] After the disappearance of raw materials as monitored by LCMS, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 8 g of 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-formaldehyde.

[0522] MS (ESI) M / Z: 314.0 [M+H] +< .

[0523] Step G: 7-(4-Methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-formaldehyde (8 g, 25.56 mmol) was dissolved in N,N-dimethylformamide (128 mL) at room temperature. Subsequently, N-chlorosuccinimide (5.12 g, 38.34 mmol) was slowly added to the above solution. The reaction system was then stirred at 50°C for 2 hours.

[0524] After the disappearance of raw materials as monitored by LCMS, ice water (500 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated aqueous salt solution (100 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.5 g of 5-chloro-7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-formaldehyde.

[0525] MS (ESI) M / Z: 348.0 [M+H] +< .

[0526] Step H: 5-Chloro-7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-formaldehyde (3.5 g, 10.09 mmol) and sulfur powder (65 mg, 2.02 mmol) were dissolved in ammonia / methanol solution (4 mol / L, 34 mL) at room temperature. The reaction system was then stirred at 80°C for 6 hours.

[0527] After the disappearance of raw materials as monitored by LCMS, ice water (40 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated saline (100 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.9 g of 4-(4-methoxybenzyl)-6-(methylthio)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine.

[0528] MS (ESI) M / Z: 343.0 [M+H] +< .

[0529] Step I: 4-(4-Methoxybenzyl)-6-(methylthio)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine (2.9 g, 8.48 mmol) was dissolved in dry dichloromethane solution (43 mL) at room temperature. Subsequently, m-chloroperoxybenzoic acid (3.22 g, 18.66 mmol) was slowly added to the above reaction system at -78°C. The reaction system was then stirred at room temperature for 4 hours.

[0530] After the disappearance of raw materials as monitored by LCMS, ice water (100 mL) was added to the reaction solution for quenching. The mixed solution was extracted with dichloromethane (60 mL × 3 times), and the organic phases were combined and then washed with saturated saline (100 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.8 g of 4-(4-methoxybenzyl)-6-(methylsulfonyl)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine.

[0531] MS (ESI) M / Z: 375.0 [M+H] +< .

[0532] Step J: 4-(4-Methoxybenzyl)-6-(methylsulfonyl)-4H-isothiazolo[5',4':4,5]pyrrolo][2,3-d]pyrimidine (1.8 g, 4.81 mmol) was dissolved in dry 1,4-dioxane solution (16 mL) at room temperature. Subsequently, an ammonia / methanol solution (4 mol / L, 48 mL) was added to the above solution. The reaction system was then stirred at 80°C for 4 hours.

[0533] After the disappearance of raw materials as monitored by LCMS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 840 mg of 4-(4-methoxybenzyl)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidin-6-amine.

[0534] MS (ESI) M / Z: 312.0 [M+H] +< .

[0535] Step K: 4-(4-Methoxybenzyl)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidin-6-amine (840 mg, 2.70 mmol) was dissolved in dry dichloromethane solution (68 mL) at room temperature. Subsequently, trimethylchlorosilane (910 mg, 8.37 mmol) and tert-butyl nitrite (1.37 g, 13.23 mmol) were successively added to the above solution under the condition of an ice-water bath. The reaction system was then stirred at room temperature for 16 hours.

[0536] After the disappearance of raw materials as monitored by LCMS, ice water (40 mL) was added to the reaction solution for quenching. The mixed solution was extracted with dichloromethane (60 mL × 3 times), the organic phases were combined and then washed with saturated saline (100 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 390 mg of 6-chloro-4-(4-methoxybenzyl)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine.

[0537] MS (ESI) M / Z: 331.0 [M+H] +< .

[0538] Step L: 6-Chloro-4-(4-methoxybenzyl)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine (390 mg, 1.18 mmol) was dissolved in trifluoromethanesulfonic acid (8 mL) at room temperature. The reaction system was then stirred at 65°C for 2 hours.

[0539] After the disappearance of raw materials as monitored by LCMS, ice water (10 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated saline (60 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 200 mg of crude 6-chloro-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine.

[0540] MS (ESI) M / Z: 211.0 [M+H] +< .

[0541] Step M: 6-Chloro-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine (200 mg, 0.95 mmol), 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (303 mg, 0.95 mmol) and potassium carbonate (263 mg, 1.90 mmol) were dissolved in N,N-dimethylformamide (5 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 50°C for 2 hours.

[0542] After the disappearance of raw materials as monitored by LCMS, ice water (50 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated saline (60 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 170 mg of 6-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4H-isothiazolo [5',4':4,5]py rrolo[2,3-d]pyrimidine.

[0543] MS (ESI) M / Z: 449.0 [M+H] +< .

[0544] Step N: 6-Chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4H-isothiazolo[5',4':4,5]py rrolo[2,3-d]pyrimidine (170 mg, 0.38 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boric acid (110 mg, 0.57 mmol), cesium carbonate (186 mg, 0.57 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]pall adium(II) (60 mg, 0.08 mmol) were dissolved in 1,4-dioxane / water (2.7 mL / 0.3 mL) at room temperature. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and the reaction system was reacted for 2 hours under the microwave condition of 100°C.

[0545] After the disappearance of raw materials as monitored by LCMS, ice water (50 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (60 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product was collected to obtain 17.95 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4H-isothiazolo[5',4':4,5]pyrrolo[2,3-d]pyrimidine.

[0546] MS (ESI) M / Z: 563.6 [M+H] +< .

[0547] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.73 (s, 1H), 9.08 (s, 1H), 8.71 (s, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 5.82 (s, 2H), 3.88 (s, 3H), 3.73 (s, 3H), 1.77-1.68 (m, 1H), 1.10-1.04 (m, 2H), 0.90-0.83 (m, 2H).Example 15: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]i midazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indol-7-nitrile

[0548] Operation steps:

[0549] Step A: 5-Bromo-2-chloropyrimidin-4-amine (108 g, 518 mmol) was dissolved in 1,4-dioxane / water (2119 mL / 235 mL) under nitrogen protection at room temperature. Subsequently, 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (150 g, 570 mmol) and sodium carbonate (110 g, 1036 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (38 g, 46.6 mmol) were sequentially added to the above solution. The reaction system was then stirred at 90°C for 16 hours.

[0550] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered, the filtrate was collected and concentrated under reduced pressure. The residue was pulped with ethyl acetate / petroleum ether, and the filter cake was pulped again with acetonitrile / water to obtain 94.6 g of crude 4-(4-amino-2-chloropyrimidin-5-yl)-3-chlorobenzonitrile.

[0551] MS (ESI) M / Z: 265.0 [M+H] +< .

[0552] Step B: 4-(4-Amino-2-chloropyrimidin-5-yl)-3-chlorobenzonitrile (94.6 g, 358 mmol) was dissolved in 1,4-dioxane / water (1394 mL / 232 mL) under nitrogen protection at room temperature. Subsequently, (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (69.5 g, 358 mmol), cesium carbonate (233 g, 716 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]pall adium(II) (36.5 g, 46.5 mmol) were added to the above solution successively. The reaction system was then stirred at 90°C for 16 hours.

[0553] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and concentrated under reduced pressure, and the residue was pulped with ethyl acetate / petroleum ether, and the filter cake was rinsed with water and dried to obtain 118 g of crude 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyrimido[4,5-b]indol-7-nitrile.

[0554] MS (ESI) M / Z: 343.2 [M+H] +< .

[0555] Step C: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyrimido[4,5-b]indol-7-nitrile (53.8 g, 157.2 mmol) was dissolved in N,N-dimethylformamide (436 mL) at room temperature. Subsequently, cesium carbonate (114 g, 349.2 mmol) and 9-(chloromethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azapine (26.2 g, 87.3 mmol) were added to the reaction system successively. The reaction system was then stirred at 45°C for 16 hours.

[0556] After the disappearance of raw materials as monitored by LCMS, the reaction solution was added to water (900 mL) to precipitate a solid, and the obtained solid was purified by silica gel column chromatography to obtain 20.42 g of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imid azo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indol-7-nitrile.

[0557] MS (ESI) M / Z: 607.2 [M+H] +< .

[0558] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.72 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 0.8 Hz, 1H), 7.33 (dd, J = 8.0, 1.6 Hz, 1H), 5.81 (s, 2H), 3.95 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H), 2.60 (t, J = 7.0 Hz, 2H), 2.27-2.15 (m, 2H), 1.77-1.67 (m, 1H), 1.10-1.02 (m, 2H), 0.88-0.77 (m, 2H).Example 16: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0559] Operation steps:

[0560] Step A: Methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate (1 g, 5.26 mmol) was dissolved in methanol (27.5 mL) at room temperature. Subsequently, sodium borohydride (420 mg, 10.53 mmol) was slowly added to the above solution at 0°C. Then, the reaction system was stirred at room temperature for 1 hour.

[0561] After the disappearance of raw materials as monitored by LCMS, the reaction solution was slowly added dropwise into ice water (50 mL) for quenching. The resultant was filtered, the filtrate was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and then washed with saturated saline (50 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1 g of methyl 1-hydroxy-2,3-dihydro-1H-indene-5-carboxylate.

[0562] MS(ESI) M / Z: 193.1 [M+H] +< .

[0563] Step B: Methyl 1-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (710 mg, 3.68 mmol), 3,4-dihydro-2H-pyran (621.25 mg, 7.40 mmol) and pyridinium p-toluenesulfonate (95 mg, 0.37 mmol) were dissolved in dichloromethane (18.50 mL) at room temperature under nitrogen protection. The reaction system was then stirred at 60°C for 1 hour.

[0564] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 850 mg of methyl 1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-indene-5-carboxylate.

[0565] MS (ESI) M / Z: 299.2 [M+23] +< .

[0566] Step C: Methyl 1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-indene-5-carboxylate (850 mg, 2.90 mmol) was dissolved in tetrahydrofuran (15.50 mL) at 0°C under nitrogen protection. Subsequently, lithium aluminum hydride (2.5 mL, 6.18 mmol) was slowly added to the above solution. The reaction system was then stirred at room temperature for 1 hour.

[0567] After the disappearance of raw materials as monitored by LCMS, the reaction solution was slowly added dropwise into ice water (100 mL) for quenching. The resultant was filtered, the filtrate was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and then washed with saturated salt aqueous solution (100 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 690 mg of (1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-5-yl)methanol.

[0568] MS (ESI) M / Z: 271.2 [M+H] +< .

[0569] Step D: (1-((Tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-5-yl)methanol (690 mg, 2.78 mmol) and manganese dioxide (2.42 g, 27.82 mmol) were dissolved in dichloromethane (14 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 60°C for 1 hour.

[0570] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered while it was hot, and the filtrate was concentrated under reduced pressure to obtain 690 mg of 1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-5-formaldehyde.

[0571] MS (ESI) M / Z: 247.2 [M+H] +< .

[0572] Step E: 3,3-Dibromo-1,1,1-trifluoropropane-2-one (833.05 mg, 3.09 mmol) and sodium acetate (460 mg, 5.61 mmol) were dissolved in water (14 mL) at room temperature, and the solution was heated to 90°C and stirred for 0.5 hour. Subsequently, the temperature was lowered to 0°C, and a mixed solution of 1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-indene-5-formaldehyde (690 mg, 2.80 mmol) in aqueous ammonia / methanol (49 mL / 15 mL) was added to the above solution. The reaction system was then stirred at room temperature for 16 hours.

[0573] After the disappearance of raw materials as monitored by LCMS, the reaction solution was slowly added dropwise into ice water (200 mL) for quenching. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and then washed with saturated saline (100 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 590 mg of 2-(1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-5-yl)-4-(trifluoromethyl)-1H-imidazo le.

[0574] MS (ESI) M / Z: 353.2 [M+H] +< .

[0575] Step F: 2-(1-((Tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-5-yl)-4-(trifluoromethyl)-1H-imidaz ole (590 mg, 1.67 mmol) and potassium carbonate (461.30 mg, 3.34 mmol) were dissolved in N,N-dimethylformamide (8.40 mL) at room temperature. Subsequently, methyl iodide (617.08 mg, 4.35 mmol) was added to the above solution at 0°C. The reaction system was then stirred at room temperature for 4 hours.

[0576] After the disappearance of raw materials as monitored by LCMS, the reaction solution was slowly added dropwise into ice water (100 mL) for quenching. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and then washed with saturated saline (50 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 400 mg of 1-methyl-2-(1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-5-yl)-4-(trifluoromethyl)-1 H-imidazole.

[0577] MS (ESI) M / Z: 367.2 [M+H] +< .

[0578] Step G: 1-Methyl-2-(1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-5-yl)-4-(trifluoromethyl)-1 H-imidazole (400 mg, 1.09 mmol) and p-toluenesulfonic acid (41.53 mg, 0.22 mmol) were dissolved in methanol (6 mL) under nitrogen protection at room temperature, and the solution was heated to 60°C and stirred for 2 hours.

[0579] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 180 mg of 5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-ol.

[0580] MS (ESI) M / Z: 283.1 [M+H] +< .

[0581] Step H: 5-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-ol (80 mg, 0.28 mmol), 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine (90.21 mg, 0.28 mmol) and triphenylphosphine (111.49 mg, 0.43 mmol) were dissolved in anhydrous tetrahydrofuran (1.5 mL) under nitrogen protection at room temperature. Subsequently, diisopropyl azodicarboxylate (85.96 mg, 0.43 mmol) was slowly added dropwise to the above solution at 0°C. The reaction system was then stirred at room temperature for 1 hour.

[0582] After the disappearance of raw materials as monitored by LCMS, water (40 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (25 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. 28.22 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl) -2,3-dihydro-1H-inden-1-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine was obtained.

[0583] MS (ESI) M / Z: 583.3 [M+H] +< .

[0584] 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 8.71 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.53-8.22 (m, 2H), 7.94 (s, 1H), 7.80 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.92 (t, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.47-3.36 (m, 1H), 3.27-3.14 (m, 1H), 2.86-2.75 (m, 1H), 2.71-2.57 (m, 1H), 1.80-1.68 (m, 1H), 1.12-1.00 (m, 2H), 0.93-0.80 (m, 2H).Example 17: 9-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidi n-9-yl)methyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0585] Operation steps:

[0586] Step A: (2-(Trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methanol (70 mg, 0.25 mmol), 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine (79 mg, 0.25 mmol) and triphenylphosphine (97 mg, 0.37 mmol) were dissolved in dry tetrahydrofuran (1.5 mL) under nitrogen protection at room temperature. Subsequently, diisopropyl azodicarboxylate (75 mg, 0.37 mmol) was slowly added dropwise to the above solution at 0°C. The reaction system was then stirred at room temperature for 1 hour.

[0587] After the disappearance of raw materials as monitored by LCMS, ice water (20 mL) was added to the above reaction solution for quenching, and the mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and then washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. 48.59 mg of 9-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyridino [4',3':4,5]pyrrolo [2,3-d]pyrimidin-9-y l)methyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was obtained.

[0588] MS (ESI) M / Z: 585.2 [M+H] +< .

[0589] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 9.27 (s, 1H), 8.73 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.20 (dd, J = 8.4, 1.6 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 5.80 (s, 2H), 4.47-4.38 (m, 4H), 3.89 (s, 3H), 1.79-1.70 (m, 1H), 1.13-1.04 (m, 2H), 0.93-0.85 (m, 2H).Example 18: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-5,6-dihydrobenzo[f]imida zo[1,2-d][1,4]oxazepin-9-yl)methyl)-9H-pyrimido[4,5-b]indol-7-carbonitrile

[0590] Operation steps:

[0591] Step A: Methyl 3-hydroxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.13 g, 3.95 mmol) and cesium carbonate (3.9 g, 11.85 mmol) were dissolved in acetonitrile (20 mL) at room temperature, and the resultant was stirred for 1 hour. Subsequently, 1,2-dibromoethane (3.7 g, 19.76 mmol) was added to the above reaction system, the temperature was raised to 60°C, and the mixture was stirred for 12 hours.

[0592] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 453 mg of methyl 2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-formate.

[0593] MS (ESI) M / Z: 313.2 [M+H] +< .

[0594] Step B: Methyl 2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-formate (453 mg, 1.45 mmol) was dissolved in tetrahydrofuran (7.3 mL) at 0°C under nitrogen protection. Subsequently, lithium aluminum hydride (1.2 mL, 2.9 mmol) was slowly added dropwise to the above solution, the temperature was raised to room temperature, and stirring was continued for 30 minutes.

[0595] After the disappearance of raw materials as monitored by LCMS, ice water (50 mL) was added to the reaction solution for quenching, and the filter cake was washed with ethyl acetate (20 mL× 2 times). The filtrate was collected and layered, and the water phase was extracted with ethyl acetate (30 mL × 3 times). Organic phases were combined and then washed with saturated saline (40 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 200 mg of (2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methanol.

[0596] MS (ESI) M / Z: 285.3 [M+H] +< .

[0597] Step C: (2-(Trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methanol (50 mg, 0.18 mmol), triphenylphosphine (92 mg, 0.35 mmol) and 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyrimido[4,5-b]indol-7-carbonitrile (90 mg, 0.26 mmol) were dissolved in dry tetrahydrofuran (4.9 mL) at 0°C under nitrogen protection. Subsequently, diisopropyl azodicarboxylate (71 mg, 0.35 mmol) was slowly added dropwise to the above solution. The reaction system was then stirred at room temperature for 1 hour.

[0598] After the disappearance of raw materials as monitored by LCMS, ice water (50 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. 38.75 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1 ,2-d][1,4]oxazepin-9-yl)methyl)-9H-pyrimido[4,5-b]indol-7-carbonitrile was obtained.

[0599] MS (ESI) M / Z: 609.2 [M+H] +< .

[0600] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 8.72 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.52 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.4, 1.6 Hz, 1H), 7.03 (s, 1H), 5.76 (s, 2H), 4.42 (s, 4H), 3.88 (s, 3H), 1.79-1.70 (m, 1H), 1.12-1.04 (m, 2H), 0.92-0.82 (m, 2H).Example 19: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imid azol-2-yl)benzyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0601] Operation steps:

[0602] Step A: Methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2 g, 7.4 mmol) was dissolved in N,N-dimethylformamide (37 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and potassium carbonate (2.05 g, 14.8 mmol) and methyl iodide-D 3 (1.29 g, 8.89 mmol) were added successively. Then, the reaction system was stirred at room temperature for 1 hour.

[0603] After the disappearance of raw materials as monitored by LCMS, water (200 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined and then washed with saturated saline (80 mL × 2 times). The organic phases were combined and the residue was purified by silica gel column chromatography to obtain 1.6 g of methyl 4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate.

[0604] MS (ESI) M / Z: 288.3 [M+H] +< .

[0605] Step B: Methyl 4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.6 g, 5.57 mmol) was dissolved in tetrahydrofuran (28 mL) at 0°C under nitrogen protection. Subsequently, 2 M lithium aluminum hydride solution (4.8 mL) was slowly added dropwise to the above solution. Then the reaction system was stirred for 30 minutes at room temperature.

[0606] After the disappearance of raw materials as monitored by LCMS, water (100 mL) was added to the reaction solution for quenching. The mixture was filtered, and the residue was rinsed with ethyl acetate (70 mL × 2 times). The filtrate was collected and layered. The aqueous phase was extracted with ethyl acetate (60 mL × 3 times), and all organic phases were combined and then washed with saturated saline (50 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.34 g of (4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol.

[0607] MS (ESI) M / Z: 260.2 [M+H] +< .

[0608] Step C: (4-(1-(Methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (300 mg, 1.16 mmol) was dissolved in dichloromethane (5.8 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and triphenylphosphine (607 mg, 2.32 mmol), sodium bicarbonate (187 mg, 1.16 mmol) and carbon tetrabromide (767 mg, 2.32 mmol) were added successively. The reaction system was then stirred at room temperature for 2 hours.

[0609] After the disappearance of raw materials as monitored by LCMS, water (30 mL) was added to the reaction solution for quenching. The mixed solution was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (30 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 210 mg of 2-(4-(bromomethyl)phenyl)-1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazole.

[0610] MS (ESI) M / Z: 322.0 [M+H] +< .

[0611] Step D: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine (74 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (1.2 mL) at 0°C under nitrogen protection. Subsequently, sodium hydride (37 mg, 0.88 mmol) was added to the above solution, and the resultant was stirred for 20 minutes. Then, 2-(4-(bromomethyl)phenyl)-1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazole (70 mg, 0.22 mmol) was added, and the mixture was raised to room temperature and stirred for 30 minutes.

[0612] After the disappearance of raw materials as monitored by LCMS, water (30 mL) was added to the reaction solution for quenching. The mixed solution was washed with ethyl acetate (10 mL × 2 times), and the organic phases were combined and then washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 25.35 mg of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine was obtained.

[0613] MS (ESI) M / Z: 560.3 [M+H] +< .

[0614] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.30 (s, 1H), 8.73 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.35 (dd, J = 5.2, 0.8 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 5.88 (s, 2H), 3.89 (s, 3H), 1.79-1.70 (m, 1H), 1.12-1.04 (m, 2H), 0.92-0.82 (m, 2H).Example 20: 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyridi no[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0615] Operation steps:

[0616] Step A: (2-Isopropylphenyl)boric acid (170 mg, 1.04 mmol), 2-chloro-5-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (400 mg, 1.04 mmol), cesium carbonate (676 mg, 2.07 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]pall adium(II) (163 mg, 0.21 mmol) were dissolved in 1,4-dioxane / water (4.40 mL / 0.74 mL) at room temperature. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and the reaction system was stirred for 8 hours under the microwave condition of 90°C.

[0617] After the disappearance of raw materials as monitored by LCMS, ice water (20 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 85 mg of 9-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine.

[0618] MS(ESI) M / Z: 439.2 [M+H] +< .

[0619] Step B: 9-(2,4-Dimethoxybenzyl)-2-(2-isopropylphenyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine (80 mg, 0.21 mmol) was dissolved in trifluoroacetic acid (3 mL) at room temperature. The reaction system was then stirred for 12 hours.

[0620] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 76 mg of 2-(2-isopropylphenyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine.

[0621] MS (ESI) M / Z: 289.1 [M+H] +< .

[0622] Step C: 2-(2-Isopropylphenyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine (70 mg, 0.24 mmol) was dissolved in dry N,N-dimethylformamide (1.5 mL) at 0°C under nitrogen protection. Subsequently, sodium hydride (58 mg, 0.97 mmol) was added to the above solution, and the resultant was stirred for 20 minutes. Then, 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (77 mg, 0.24 mmol) was added, and the mixture was raised to room temperature and stirred for 10 minutes.

[0623] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC. The product was collected to obtain 11.73 mg of 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyridino[ 4',3': 4,5]pyrrolo[2,3-d]pyrimidine.

[0624] MS (ESI) M / Z: 527.2 [M+H] +< .

[0625] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 9.22 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.33 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.54-7.43 (m, 4H), 7.37-7.30 (m, 1H), 5.89 (s, 2H), 3.72 (s, 3H), 3.67-3.55 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).Example 21: 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0626] Operation steps:

[0627] Step A: (2-Isopropylpyridin-3-yl)boric acid (500 mg, 2.02 mmol), 2-chloro-5-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (790 mg, 2.02 mmol), cesium carbonate (1.32 g, 04.05 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]pall adium(II) (320 mg, 0.41 mmol) were dissolved in 1,4-dioxane / water (8.70 mL / 1.45 mL) at room temperature. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and the reaction system was stirred for 16 hours under the microwave condition of 90°C.

[0628] After the disappearance of raw materials as monitored by LCMS, ice water (20 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 235 mg of 9-(2,4-dimethoxybenzyl)-2-(2-isopropylpyridin-3-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidi ne.

[0629] MS(ESI) M / Z: 440.2 [M+H] +< .

[0630] Step B: 9-(2,4-Dimethoxybenzyl)-2-(2-isopropylpyridin-3-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimid ine (210 mg, 0.48 mmol) was dissolved in trifluoroacetic acid (4 mL) at room temperature. The reaction system was then stirred for 16 hours.

[0631] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 167 mg of 2-(2-isopropylpyridin-3-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine.

[0632] MS (ESI) M / Z: 291.2 [M+H] +< .

[0633] Step C: 2-(2-Isopropylpyridin-3-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine (157 mg, 0.54 mmol) was dissolved in dry N,N-dimethylformamide (2.7 mL) at 0°C under nitrogen protection. Subsequently, sodium hydride (87 mg, 2.17 mmol) was added to the above solution and stirred for 20 minutes. Then, 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (172 mg, 0.54 mmol) was added, and the mixture was raised to room temperature and stirred for 10 minutes.

[0634] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The product was collected to obtain 62.29 mg of 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyri dino[4',3':4,5]pyrrolo[2,3-d]pyrimidine.

[0635] MS (ESI) M / Z: 528.2 [M+H] +< .

[0636] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.24 (s, 1H), 8.68 (dd, J = 4.6, 1.8 Hz, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.35 (dd, J = 5.2, 0.4 Hz, 1H), 8.19 (dd, J = 7.6, 1.8 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.40 (dd, J = 8.0, 4.8 Hz, 1H), 5.91 (s, 2H), 3.86-3.75 (m, 1H), 3.73 (s, 3H), 1.22 (d, J = 6.4 Hz, 6H).Example 22: 2-(1-cyclobutyl-4-methoxy-1H-pyrazol-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0637] Operation steps:

[0638] Step A: 4-Methoxy-1H-pyrazole (6.0 g, 61.2 mmol) and potassium carbonate (33.8 g, 244.8 mmol) were dissolved in N,N-dimethylformamide (250 mL) at room temperature, and the solution was stirred for 30 min. Subsequently, cyclobutyl bromide (24.6 g, 183.6 mmol) was added dropwise to the above solution, and the solution was heated to 70°C and stirred for 24 hours.

[0639] After the disappearance of raw materials as monitored by LCMS, ice water (800 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (250 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated aqueous salt solution (250 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 600 mg of 1-cyclobutyl-4-methoxy-1H-pyrazole.

[0640] MS(ESI) M / Z: 153.2 [M+H] +< .

[0641] Step B: 1-Cyclobutyl-4-methoxy-1H-pyrazole (580 mg, 3.81 mmol) was dissolved in dry tetrahydrofuran (40 mL) at -78°C under nitrogen protection. Subsequently, 2.5 M n-butyl lithium solution (2.0 mL, 5.0 mmol) was slowly added dropwise to the above solution, and the mixture was stirred for 1 hour. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (922 mg, 4.95 mmol) was added dropwise, and the mixture was raised to room temperature and stirred for 2 hours.

[0642] After the disappearance of raw materials as monitored by LCMS, ice water (20 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 600 mg of (1-cyclobutyl-4-methoxy-1H-pyrazol-5-yl)boric acid.

[0643] MS(ESI) M / Z: 197.2 [M+H] +< .

[0644] Step C: (1-Cyclobutyl-4-methoxy-1H-pyrazol-5-yl)boric acid (84 mg, 0.43 mmol), 2-chloro-5-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (168 mg, 0.43 mmol), cesium carbonate (281 mg, 0.86 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]pall adium(II) (84 mg, 0.08 mmol) were dissolved in 1,4-dioxane / water (1.85 mL / 0.31 mL) at room temperature. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and the reaction system was stirred for 12 hours under the microwave condition of 90°C.

[0645] After the disappearance of raw materials as monitored by LCMS, ice water (20 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 115 mg of 2-(1-cyclobutyl-4-methoxy-1H-pyrazol-5-yl)-9-(2,4-dimethoxybenzyl)-9H-pyridino[4',3':4,5]pyrro lo[2,3-d]pyrimidine.

[0646] MS(ESI) M / Z: 471.2 [M+H] +< .

[0647] Step D: 2-(1-Cyclobutyl-4-methoxy-1H-pyrazol-5-yl)-9-(2,4-dimethoxybenzyl)-9H-pyridino[4',3':4,5]pyrr olo[2,3-d]pyrimidine (110 mg, 0.23 mmol) was dissolved in trifluoroacetic acid (3 mL) at room temperature, the solution was then stirred at room temperature for 12 hours.

[0648] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 100 mg of 2-(1-cyclobutyl-4-methoxy-1H-pyrazol-5-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine.

[0649] MS (ESI) M / Z: 321.2 [M+H] +< .

[0650] Step E: 2-(1-Cyclobutyl-4-methoxy-1H-pyrazol-5-yl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine (100 mg, 0.31 mmol) was dissolved in dry N,N-dimethylformamide (1.6 mL) at 0°C under nitrogen protection. Subsequently, sodium hydride (50 mg, 1.25 mmol) was added to the above solution, and the resultant was stirred for 20 minutes. Then, 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (99 mg, 0.31 mmol) was added, and the mixture was raised to room temperature and stirred for 10 minutes.

[0651] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 15.44 mg of 2-(1-cyclobutyl-4-methoxy-1H-pyrazol-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl )benzyl)-9H-pyridino[4',3':4,5]pyrrolo[2,3-d]pyrimidine was obtained.

[0652] MS (ESI) M / Z: 559.2 [M+H] +< .

[0653] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 9.27 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.29 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 5.89 (s, 2H), 5.68-5.56 (m, 1H), 3.84 (s, 3H), 3.72 (s, 3H), 2.61-2.53 (m, 2H), 2.31-2.19 (m, 2H), 1.79-1.54 (m, 2H).Example 23: N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidaz ol-2-yl)benzyl)-9H-pyrimido[4,5-b]indol-7-yl)-N-methylmethanesulfonamide

[0654] Operation steps:

[0655] Step A: N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl)benzyl)-9H-pyrimido[4,5-b]indol-7-yl)methanesulfonamide (80 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1.2 mL) at 0°C under nitrogen protection. Subsequently, sodium hydride (8.8 mg, 0.22 mmol) was added to the above solution, and the resultant was stirred for 0.5 hour. Then, methyl iodide (31 mg, 0.22 mmol) was slowly added dropwise, and the solution was heated to room temperature and stirred for 10 minutes.

[0656] After the disappearance of raw materials as monitored by LCMS, water (20 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 42.99 mg of N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl)benzyl)-9H-pyrimido[4,5-b]indol-7-yl)-N-methylmethanesulfonamide was obtained.

[0657] MS (ESI) M / Z: 663.2 [M+H] +< .

[0658] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.71 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.54-7.45 (m, 3H), 5.80 (s, 2H), 3.88 (s, 3H), 3.71 (s, 3H), 3.36 (s, 3H), 3.00 (s, 3H), 1.76-1.67 (m, 1H), 1.10-1.01 (m, 2H), 0.89-0.81 (m, 2H).Example 24: N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo [c]imidazo[1,2-a]azepan-9-yl)methyl)-9H-pyrimido[4,5-b]indol-7-yl)methanesulfonamide

[0659] Operation steps:

[0660] Step A: N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyrimido[4,5-b]indol-7-yl)-N-((2-(trimethylsil yl)ethoxy)methyl)methanesulfonamide (366 mg, 0.68 mmol) was dissolved in N,N-dimethylformamide (6.8 mL) under nitrogen protection at room temperature. Subsequently, the above solution was cooled to 0°C, and sodium hydride (48.8 mg, 1.22 mmol) was slowly added, and the resultant was stirred for 0.5 hour. Then 9-(bromomethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepane (233 mg, 0.68 mmol) was added, and the mixture was heated to room temperature and stirred for 10 minutes.

[0661] After the disappearance of raw materials as monitored by LCMS, water (20 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 350 mg of N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]i midazo[1,2-a]azepan-9-yl)methyl)-9H-pyrimido[4,5-b]indol-7-yl)-N-(2-(trimethylsilyl)ethoxy)met hyl)methanesulfonamide.

[0662] MS (ESI) M / Z: 805.2 [M+H] +< .

[0663] Step B: N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]i midazo[1,2-a]azepan-9-yl)methyl)-9H-pyrimido[4,5-b]indol-7-yl)-N-(2-(trimethylsilyl)ethoxy)met hyl)methanesulfonamide (350 mg, 0.43 mmol) was dissolved in dichloromethane (4 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and trifluoroacetic acid (4 mL) was slowly added dropwise. The reaction system was then heated to room temperature and stirred for 1 hour.

[0664] After the disappearance of raw materials as monitored by LCMS, water (30 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated sodium bicarbonate solution (15 mL) and saturated saline (30 mL × 2 times) successively. The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by dichloromethane / ethyl acetate to obtain 168.30 mg of N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]i midazo[1,2-a]azepan-9-yl)methyl)-9H-pyrimido[4,5-b]indol-7-yl)methanesulfonamide.

[0665] MS (ESI) M / Z: 675.2 [M+H] +< .

[0666] 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.12 (s, 1H), 9.56 (s, 1H), 8.71 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.39 (s, 1H), 7.27-7.23 (m, 2H), 5.70 (s, 2H), 3.95 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H), 3.04 (s, 3H), 2.61 (t, J = 7.0 Hz, 2H), 2.28-2.15 (m, 2H), 1.77-1.67 (m, 1H), 1.10-1.02 (m, 2H), 0.90-0.79 (m, 2H).Examples 25 to 140

[0667] Target compounds in the following Table 1 were prepared by referring to the synthesis method of Example 8 above: Table 1Example Compound Structural formula 1< HNMR MS (ESI)M / Z :[M+H] +< 25Compound 12 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.77 (s, 1H), 8.97 (d, J = 0.8 Hz, 1H), 8.72 (s, 1H), 8.15 (d, J = 0.8 Hz, 1H), 8.13 - 8.03 (m, 2H), 7.52 - 7.47 (m, 4H), 5.87 (s, 2H), 4.43 - 4.33 (m, 1H), 3.87 (s, 3H), 1.79 - 1.68 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H), 1.10 - 1.02 (m, 2H), 0.89 - 0.79 (m, 2H).609.026Compound 14 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.84 (s, 1H), 8.71 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 8.00 (dd, J = 8.0, 1.2 Hz, 1H), 7.51(d, J = 8.4 Hz, 2H), 7.45 (d, J =8.4 Hz, 2H), 5.94 (s, 2H), 4.46 - 4.31 (m, 1H), 3.87 (s, 3H), 3.34 (s, 3H), 1.79 - 1.65 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H), 1.10 - 1.00 (m, 2H), 0.89 - 0.75 (m, 2H).661.827Compound 15 1< HNMR (400 MHz, DMSO-d 6 ): δ 9.67 (s, 1H), 8.71 (s, 1H), 8.26 (dd, J = 8.8, 2.8 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.91 (dd, J = 9.2, 4.4 Hz, 1H), 7.58 - 7.39 (m, 5H), 5.81 (s, 2H), 4.46 - 4.28 (m, 1H), 3.87 (s, 3H), 1.78 - 1.66 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H), 1.10 - 1.00 (m, 2H), 0.89 - 0.78 (m, 2H).602.228Compound 16 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.66 (s, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.72 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.21 (d,J = 1.2 Hz, 1H), 8.02 - 7.90 (m, 3H), 7.66 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 5.83 (s, 2H), 5.70 - 5.58 (m, 1H), 3.89 (s, 3H), 1.80 - 1.70 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.11 - 1.03 (m, 2H), 0.93 - 0.82 (m, 2H).585.229Compound 17 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.66 (s, 1H), 8.70 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.51 (s, 4H), 7.44 (t, J = 7.64 Hz, 1H), 6.72 (s, 1H), 5.82 (s, 2H), 3.87 (s, 3H), 2.27 (s, 3H), 1.78 - 1.66 (m, 1H), 1.11 - 0.99 (m, 2H), 0.91 - 0.78 (m, 2H).556.230Compound 18 1< H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.71 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 1.2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.33 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.84 (dd, J = 7.8, 0.5 Hz, 1H), 5.79 (s, 2H), 4.00 - 3.90 (m, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 1.74 - 1.64 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H), 1.10 - 1.02 (m, 2H), 0.88 - 0.79 (m, 2H).614.331Compound 19 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.67 (s, 1H), 8.71 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.23 (s, 1H), 6.83 (d, J = 9.2 Hz, 1H), 5.79 (s, 2H), 3.94 - 3.87 (m, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 1.76 - 1.67 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.11 - 1.02 (m, 2H), 0.90 - 0.79 (m, 2H).632.332Compound 20 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.71 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.70 - 7.61 (m, 3H), 7.52 - 7.42 (m, 3H), 5.83 (s, 2H), 5.39 - 5.27 (m, 1H), 3.72 (s, 3H), 1.40 (d, J = 6.4 Hz, 6H).550.333Compound 21 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.81 (s, 1H), 8.72 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.86 (dd, J =8.0, 1.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 5.84 (s, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 1.78 - 1.66(m, 1H), 1.10 - 1.02 (m, 2H), 0.89 - 0.81 (m, 2H).581.034Compound 22 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.84 (s, 1H), 8.90 (s, 1H), 8.72 (s, 1H), 8.15 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.55 - 7.42 (m, 4H), 5.88 (s, 2H), 4.43 - 4.33 (m, 1H), 3.88 (s, 3H), 1.78 - 1.68 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H), 1.11 - 1.01 (m, 2H), 0.90 - 0.80 (m, 2H).652.335Compound 23 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 8.71 (s, 1H), 8.37 (d, J= 7.6 Hz, 1H), 8.15 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.65 - 7.54 (m, 3H), 7.51 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 6.32 - 6.19 (m, 1H), 4.48 - 4.34 (m, 1H), 3.88 (s, 3H), 2.96 - 2.80 (m, 1H), 2.66 - 2.56 (m, 1H), 1.82 - 1.72 (m, 1H), 1.36 (d, J = 6.4 Hz, 6H), 1.12 - 1.02 (m, 2H), 0.91 - 0.82 (m, 2H), 0.77 (t, J = 7.0 Hz, 3H).612.036Compound 24 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.66 (s, 1H), 8.70 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.50 - 7.36 (m, 5H), 6.91 (s, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 2.25 (s, 3H), 1.76 - 1.66 (m, 1H), 1.10 - 1.00 (m, 2H), 0.90 - 0.76 (m, 2H),556.237Compound 25 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.40 (s, 1H), 8.70 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.90 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 9.2 Hz, 1H), 6.12 (s, 2H), 5.71 (s, 2H), 3.87 (s, 3H), 3.72 (m, 3H), 1.80 - 1.66 (m, 1H), 1.12 - 0.98 (m, 2H), 0.93 - 0.77 (m, 2H).572.138Compound 26 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.84 (s, 1H), 8.79 (dd, J = 7.6, 0.8 Hz, 1H), 8.70 (s, 1H), 8.09 (dd, J = 8.0, 1.2 Hz, 1H), 7.90 (s, 1H), 7.67 - 7.58 (m, 3H), 7.29 (d, J = 8.4 Hz, 2H), 6.08 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 1.74 - 1.63 (m, 1H), 1.07 - 1.00 (m, 2H), 0.84 - 0.77 (m, 2H).581.639Compound 27 1H NMR (400 MHz, DMSO-d 6 ): δ 9.74 (s, 1H), 8.71 (s, 1H), 8.23 (dd, J = 7.6 Hz, 0.8 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.53 - 7.45 (m, 1H), 7.45 - 7.40 (m, 1H), 7.37 (d, J = 8.4 Hz, 2H), 5.85 (s, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 1.77 - 1.68 (m, 1H), 1.09 - 1.03 (m, 2H), 0.89 - 0.81 (m, 2H).574.040Compound 28 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.72 (s, 1H), 8.71 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 8.16 (br, 1H), 7.97 (dd, J = 8.4, 1.2 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.56 (br, 1H), 7.46 (d, J = 8.4 Hz, 2H), 5.82 (s, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 1.76 - 1.69 (m, 1H), 1.09 - 1.02 (m, 2H), 0.88 - 0.81 (m, 2H).599.041Compound 29 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 9.31 (s, 1H), 8.72 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.35 (dd, J = 5.2 Hz, 0.8 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 5.89 (s, 2H), 4.45 - 4.31 (m, 1H), 3.88 (s, 3H), 1.79 - 1.68 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H), 1.10 - 1.04 (m, 2H), 0.89 - 0.81 (m, 2H).585.242Compound 30 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.78 (s, 1H), 8.71 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 1.2 Hz, 1H), 7.94 - 7.89 (m, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.51 (br, 2H), 7.43 (d, J = 8.4 Hz, 2H), 5.86 (s, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 1.79 - 1.69 (m, 1H), 1.11 - 1.02 (m, 2H), 0.89 - 0.80 (m, 2H).635.043Compound 31 1< H NMR (400 MHz, DMSO-d 6 ): δ 8.96 (s, 1H), 8.66 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 5.49 (s, 2H), 3.84 (s, 3H), 3.75 (s, 3H), 2.95 - 2.80 (m, 4H), 2.49 - 2.42 (m, 2H), 1.72 - 1.61 (m, 1H), 1.08 - 0.98 (m, 2H), 0.88 - 0.78 (m, 2H).546.344Compound 33 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.63 (s, 1H), 8.70 (s, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.26 (dd, J = 8.9, 2.6 Hz, 1H), 5.77 (s, 2H), 4.45 - 4.32 (m, 1H), 1.78 - 1.67 (m, 1H), 1.35 (d, J = 6.6 Hz, 6H), 1.10 - 1.02 (m, 2H), 0.88 - 0.81 (m, 2H).614.245Compound 34 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 8.70 (s, 1H), 8.46 (s, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.77 (s, 2H), 5.17 (s, 1H), 3.88 (s, 3H), 3.71 (s, 3H), 1.76 - 1.68 (m, 1H), 1.54 (s, 6H), 1.10 - 1.03 (m, 2H), 0.89 - 0.80 (m, 2H),614.346Compound 35 1< H NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 8.71 (s, 1H), 8.23 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 1.4 Hz, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.53 - 7.40 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 5.85 (s, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.78 - 1.67 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.11 - 1.02 (m, 2H), 0.90 - 0.79 (m, 2H).588.247Compound 36 1< H NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 8.77 (dd, J = 7.7, 1.6 Hz, 1H), 8.72 (s, 1H), 8.68 (dd, J = 5.0, 1.6 Hz, 1H), 8.17 (d, J = 1.3 Hz, 1H), 7.56 - 7.48 (m, 5H), 5.81 (s, 2H), 4.49 - 4.32 (m, 1H), 3.89 (s, 3H), 1.83 - 1.70 (m, 1H), 1.37 (d, J = 6.6 Hz, 6H), 1.12 - 1.02 (m, 2H), 0.89 - 0.79 (m, 2H).585.448Compound 37 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.88 (s, 1H), 9.04 (d, J = 1.6 Hz, 1H), 8.72 (s, 1H), 8.20 - 8.09 (m, 2H), 7.90 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 5.87 (s, 2H), 3.88 (s, 3H), 3.71 (s, 3H), 3.28 (s, 3H), 1.78 - 1.69 (m, 1H), 1.10 - 1.02 (m, 2H), 0.89 - 0.82 (m, 2H).634.249Compound 38 1< H NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 8.70 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.90 (s, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 5.79 (s, 2H), 5.22 (s, 1H), 3.87 (s, 3H), 3.72 (s, 3H), 1.77 - 1.66 (m, 1H), 1.52 (s, 3H), 1.11 - 1.02 (m, 2H), 0.89 - 0.80 (m, 2H),614.350Compound 39 1< H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.73 (s, 1H), 8.29 (d, J = 8.4, 1H), 7.96 (d, J = 7.6, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.86 - 7.79 (m, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 5.88 (s, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 1.82 - 1.67 (m, 1H), 1.13 - 1.03 (m, 2H), 0.91 - 0.80 (m, 2H).581.051Compound 40 1< H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 8.71 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.69 - 7.60 (m, 3H), 7.46 (d, J = 8.3 Hz, 2H), 7.22 (t, J = 55.8 Hz, 1H), 5.86 (s, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 1.78 - 1.67 (m, 1H), 1.10 - 1.01 (m, 2H), 0.90 - 0.75 (m, 2H).606.052Compound 41 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.81 (s, 1H), 8.71 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.78 (dd, J = 8.4, 1.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.91 (s, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 1.78 - 1.66 (m, 1H), 1.11 - 1.02 (m, 2H), 0.90 - 0.77 (m, 2H).624.353Compound 42 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.78 (s, 1H), 8.71 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.39 (s, 1H), 8.04 (dd, J = 8.2, 1.4 Hz, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 5.90 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.71 (s, 3H), 1.77 - 1.68 (m, 1H), 1.09 - 1.02 (m, 2H), 0.87 - 0.80 (m, 2H),614.254Compound 43 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.86 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.56 (s, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.88 (dd, J = 8.0, 1.2 Hz, 1H), 7.76 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 5.88 (s, 2H), 5.40 - 5.27 (m, 1H), 3.72 (s, 3H), 1.39 (d, J = 6.4 Hz, 6H).575.255Compound 44 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.76 (s, 1H), 8.69 (s, 1H), 8.42 (dd, J = 7.7, 1.1 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.70 - 7.58 (m, 3H), 7.45 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 6.12 (s, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 1.78 - 1.63 (m, 1H), 1.09 - 0.96 (m, 2H), 0.88 - 0.69 (m, 2H).590.056Compound 45 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.81 (s, 1H), 8.71 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.92 (s, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.78 - 1.66 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H), 1.09 - 1.01 (m, 2H), 0.87 - 0.78 (m, 2H).638.357Compound 46 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 8.70 (s, 1H), 8.15 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.42 - 7.32 (m, 3H), 7.24 (d, J = 8.0 Hz, 1H), 5.96 (s, 2H), 4.49 - 4.28 (m, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 1.77 - 1.64 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H), 1.12 - 0.97 (m, 2H), 0.88 - 0.77 (m, 2H).614.258Compound 47 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.91 (s, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 8.02 (dd, J = 8.0, 1.2 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.78 - 7.66 (m, 3H), 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.85 (s, 2H), 3.88 (s, 3H), 3.70 (s, 3H), 1.78 - 1.69 (m, 1H), 1.10 - 1.02 (m, 2H), 0.89 - 0.82 (m, 2H).599.359Compound 48 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.88 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 1.2 Hz, 1H), 8.01 (dd, J = 8.0, 1.2 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 5.96 (s, 2H), 5.40 - 5.27 (m, 1H), 3.72 (s, 3H), 3.34 (s, 3H), 1.38 (d, J = 6.8 Hz, 6H).628.060Compound 49 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.74 (s, 1H), 8.71 (s, 1H), 8.24 (d, J = 6.8 Hz, 1H), 7.54 - 7.31 (m, 6H), 6.91 (s, 1H), 5.87 (s, 2H), 3.86 (s, 3H), 2.25 (s, 3H), 1.78 - 1.67 (m, 1H), 1.13 - 1.00 (m, 2H), 0.90 - 0.77 (m, 2H).574.461Compound 50 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.81 (s, 1H), 8.72 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.55 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 5.85 (s, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.76 - 1.68 (m, 1H), 1.27 (t, J = 7.4 Hz, 3H), 1.09 - 1.03 (m, 2H), 0.88 - 0.80 (m, 2H).595.262Compound 51 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 8.72 (s, 1H), 8.59 (m, 2H), 8.15 (d, J = 1.2 Hz, 1H), 7.87 (dd, J = 8.0, 1.2 Hz, 1H), 7.57 - 7.48 (m, 4H), 5.86 (s, 2H), 4.43 - 4.33 (m, 1H), 3.88 (s, 3H), 1.78 - 1.69 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H), 1.10 - 1.03 (m, 2H), 0.88 - 0.80 (m, 2H).609.163Compound 52 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 8.71 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.49 - 7.36 (m, 4H), 6.91 (s, 1H), 5.94 (s, 2H), 3.85 (s, 3H), 2.25 (s, 3H), 1.76 - 1.66 (m, 1H), 1.08 - 1.01 (m, 2H), 0.85 - 0.78 (m, 2H).624.264Compound 53 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.70 (s, 1H), 8.78 (dd, J = 7.6, 1.2 Hz, 1H), 8.71 (s, 1H), 8.68 (dd, J = 5.2, 1.6 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.52 (dd, J = 8.0, 4.8 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 5.78 (s, 2H), 3.86 (s, 3H), 3.71 (s, 3H), 1.76 - 1.68 (m, 1H), 1.08 - 1.03 (m, 2H), 0.86 - 0.80 (m, 2H).557.365Compound 54 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.69 (s, 1H), 8.71 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.54 - 7.42 (m, 3H), 5.81 (s, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 1.79 - 1.64 (m, 1H), 1.13 - 0.98 (m, 2H), 0.91 - 0.76 (m, 2H).590.066Compound 55 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 9.29 (s, 1H), 8.72 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.35 (dd, J = 5.2, 1.1 Hz, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 5.88 (s, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 1.81 - 1.67 (m, 1H), 1.12 - 1.02 (m, 2H), 0.93 - 0.79 (m, 2H).557.267Compound 56 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.28 (s, 1H), 8.67 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.72 (s, 2H), 6.54 (d, J = 8.4 Hz, 1H), 5.61 (s, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 1.73 - 1.63 (m, 1H), 1.06 - 0.97 (m, 2H), 0.85 - 0.75 (m, 2H).572. 368Compound 57 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.77 (s, 1H), 9.56 (d, J = 1.0 Hz, 1H), 8.72 (s, 1H), 8.68 (d, J = 5.7 Hz, 1H), 7.93 (dd, J = 5.8, 1.0 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 5.81 (s, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 1.80 - 1.61 (m, 1H), 1.13 - 0.99 (m, 2H), 0.90 - 0.78 (m, 2H).557. 269Compound 59 1< H NMR (400 MHz, DMSO-d 6 ): δ 10.12 (s, 1H), 9.56 (s, 1H), 8.70 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.25 (dd, J = 8.5, 1.9 Hz, 1H), 5.73 (s, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 3.04 (s, 3H), 1.79 - 1.65 (m, 1H), 1.11 - 1.02 (m, 2H), 0.91 - 0.81 (m, 2H).649.070Compound 61 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 9.26 (d, J = 0.8 Hz, 1H), 8.72 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.35 (dd, J = 5.2, 0.8 Hz, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.35 (dd, J = 8.0, 1.6 Hz, 1H), 5.84 (s, 2H), 3.95 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 2.61 (t, J = 7.0 Hz, 2H), 2.26 - 2.15 (m, 2H), 1.79 - 1.69 (m, 1H), 1.11 - 1.03 (m, 2H), 0.89 - 0.79 (m, 2H).583.371Compound 62 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.80 (s, 1H), 8.71 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.83 (dd, J = 8.2, 1.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 5.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 5.89 (s, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 2.41 (d, J = 4.4 Hz, 3H), 1.81 - 1.67 (m, 1H), 1.12 - 1.02 (m, 2H), 0.93 - 0.77 (m, 2H).649.272Compound 63 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.71 (s, 1H), 8.78 (dd, J = 7.6, 1.6 Hz, 1H), 8.71 (s, 1H), 8.67 (dd, J = 5.0, 1.4 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.53 (dd, J = 7.8, 5.0 Hz, 1H), 7.39 (d, J = 1.2 Hz, 1H), 7.30 (dd, J = 8.0, 1.6 Hz, 1H), 5.75 (s, 2H), 3.95 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 2.60 (t, J = 6.8 Hz, 2H), 2.25 - 2.15 (m, 2H), 1.76 - 1.67 (m, 1H), 1.09 - 1.02 (m, 2H), 0.85 - 0.77 (m, 2H).583.373Compound 64 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.79 (s, 1H), 9.47 (d, J = 1.1 Hz, 1H), 8.74 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.32 (dd, J = 5.2, 1.1 Hz, 1H), 8.09 (d, J = 1.3 Hz, 1H), 7.48 (d, J = 3.8 Hz, 1H), 7.30 (d, J = 3.8 Hz, 1H), 6.02 (s, 2H), 4.78 - 4.62 (m, 1H), 3.90 (s, 3H), 1.81 - 1.70 (m, 1H), 1.39 (d, J = 6.6 Hz, 6H), 1.12 - 1.06 (m, 2H), 0.98 - 0.90 (m, 2H).579.174Compound 65 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.81 (s, 1H), 9.26 (d, J = 1.1 Hz, 1H), 8.73 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.34 (dd, J = 5.2, 1.1 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.42 (s, 1H), 7.41 (d, J = 7.9 Hz, 1H), 5.82 (s, 2H), 4.20 (t, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.13 (t, J = 7.0 Hz, 2H), 1.81 - 1.65 (m, 1H), 1.12 - 1.02 (m, 2H), 0.92 - 0.78 (m, 2H).569.275Compound 66 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 9.29 (s, 1H), 8.72 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.35 (dd, J = 5.2, 0.8 Hz, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 5.88 (s, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.78 - 1.69 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.11 - 1.03 (m, 2H), 0.90 - 0.81 (m, 2H).571.376Compound 67 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.84 (s, 1H), 9.28 (s, 1H), 8.71 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.55 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.39 - 8.31 (m, 2H), 7.91 (s, 1H), 7.68 (dd, J = 8.4, 1.2 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 6.00 (s, 2H), 3.87 (s, 3H), 1.79 - 1.68 (m, 1H) , 1.09 - 0.98 (m, 2H), 0.83 - 0.71 (m, 2H).567.277Compound 68 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.81 (s, 1H), 9.25 (d, J = 0.4 Hz, 1H), 8.73 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.33 (dd, J = 5.2, 1.2 Hz, 1H), 7.73 (d, J = 1.2 Hz, 1H), 6.65 (d, J = 3.6 Hz, 1H), 6.39 (d, J = 4.0 Hz, 1H), 5.86 (s, 2H), 4.22 (t, J = 5.8 Hz, 2H), 4.02 (t, J = 5.8 Hz, 2H), 3.86 (s, 3H), 2.01 - 1.91 (m, 2H), 1.68 - 1.59 (m, 1H), 1.12 - 1.05 (m, 2H), 0.92 - 0.83 (m, 2H).572.078Compound 69 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.79 (s, 1H), 9.33 (s, 1H), 8.74 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.33 (d, J = 5.2 Hz, 1H), 7.80 (s, 1H), 6.54 (d, J = 3.6 Hz, 1H), 6.43 (d, J = 3.6 Hz, 1H), 5.86 (s, 2H), 4.38 (t, J = 6.0 Hz, 2H), 4.25 (t, J = 5.8 Hz, 2H), 3.87 (s, 3H), 1.68 - 1.59 (m, 1H), 1.14 - 1.04 (m, 2H), 0.91 - 0.83 (m, 2H),558.279Compound 70 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 8.72 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.86 (s, 2H), 5.08 (s, 2H), 3.88 (s, 3H), 1.79 - 1.69 (m, 1H), 1.10 - 1.03 (m, 2H), 0.87 - 0.80 (m, 2H).579.880Compound 71 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 9.28 (s, 1H), 8.73 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 5.1 Hz, 1H), 8.09 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 5.89 (s, 2H), 5.09 (s, 2H), 3.89 (s, 3H), 1.83 - 1.69 (m, 1H), 1.11 - 1.02 (m, 2H), 0.93 - 0.78 (m, 2H).555.281Compound 72 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.70 (s, 1H), 8.78 (dd, J = 7.8, 1.6 Hz, 1H), 8.71 (s, 1H), 8.67 (dd, J = 4.9, 1.6 Hz, 1H), 8.08 (d, J = 1.3 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.56 - 7.48 (m, 2H), 5.80 (s, 2H), 5.07 (s, 2H), 3.87 (s, 3H), 1.81 - 1.61 (m, 1H), 1.11 - 0.99 (m, 2H), 0.87 - 0.72 (m, 2H).555.282Compound 73 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.70 (s, 1H), 8.94 (t, J = 8.0 Hz, 1H), 8.71 (s, 1H), 7.91 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 1H), 5.72 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 1.69 - 1.73 (m, 1H), 1.05 - 1.07 (m, 2H), 0.82 - 0.85 (m, 2H).575.283Compound 74 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.27 (s, 1H), 8.68 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.28 - 7.31 (m, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.62 (s, 2H), 3.86 (s, 3H), 3.72 (s, 3H), 2.95 (s, 3H), 1.69 - 1.73 (m, 1H), 1.02 - 1.05 (m, 2H), 0.82 - 0.85 (m, 2H).586.384Compound 84 1< H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.15 (d, J = 1.0 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.30 (dd, J = 5.2, 1.1 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.74 - 7.63 (m, 2H), 7.53 - 7.45 (m, 3H), 7.16 (dd, J = 7.0, 1.3 Hz, 1H), 6.74 (dd, J = 7.8, 7.0 Hz, 1H), 5.88 (s, 2H), 3.73 (s, 3H), 3.45 - 3.38 (m, 2H), 2.99 (t, J = 8.4 Hz, 2H), 2.40 (s, 3H).540.285Compound 85 1< H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.18 (d, J = 1.1 Hz, 1H), 8.63 (d, J = 5.1 Hz, 1H), 8.36 (dd,J = 5.2, 1.1 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.72 (dd, J = 7.8, 1.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.52 (dd, J = 7.4, 1.2 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 3.1 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 3.1 Hz, 1H), 5.93 (s, 2H), 3.73 (s, 3H), 3.43 (s, 3H).538.286Compound 86 1< H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.56(s, 1H), 8.70 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.51 (d,J = 8.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.25 (dd, J = 8.4, 1.9 Hz, 1H), 5.74 (s, 2H), 4.45 - 4.33 (m, 1H), 3.87 (s, 3H), 3.03 (s, 3H), 1.78 - 1.66 (m, 1H), 1.35 (d, J = 6.6 Hz, 6H), 1.11 - 1.01 (m, 2H), 0.89 - 0.77 (m, 2H).677.387Compound 87 1< H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.72 (s, 1H), 8.58 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.86 (dd, J = 8.1, 1.3 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.29 (dd, J = 8.0, 1.7 Hz, 1H), 5.84 (s, 2H), 4.20 - 4.10 (m, 1H), 3.86 (s, 3H), 3.71 - 3.57 (m, 1H), 2.81 - 2.65 (m, 1H), 2.47 - 2.35 (m, 1H), 1.85 - 1.74 (m, 1H), 1.74 - 1.63 (m, 1H), 1.11 (d, J = 6.9 Hz, 3H), 1.09 - 1.03 (m, 2H), 0.87 - 0.79 (m, 2H).586.388Compound 90 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.30 (d, J = 0.4 Hz, 1H), 8.72 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.35 (dd, J = 5.2, 1.2 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.31 (dd, J =8.0, 1.6 Hz, 1H), 5.87 (s, 2H), 4.20 - 4.10 (m, 1H), 3.87 (s, 3H), 3.70- 3.59 (m, 1H), 2.80 - 2.69 (m, 1H), 2.47 - 2.36 (m, 1H), 1.87 - 1.77 (m, 1H), 1.75 - 1.65 (m, 1H), 1.15 - 1.04 (m, 5H), 0.89 - 0.79 (m, 2H).597.289Compound 91 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.71 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.98 - 7.92 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.32 (dd, J = 7.8, 1.4 Hz, 1H), 5.76 (s, 2H), 3.94 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H), 3.36 (s, 3H), 2.99 (s, 3H), 2.60 (t, J = 6.8 Hz, 2H), 2.26 - 2.15 (m, 2H), 1.75 - 1.66 (m, 1H), 1.11 - 1.01 (m, 2H), 0.89 - 0.78 (m, 2H).689.290Compound 92 1< H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.71 (s, 1H), 8.59 (d, J = 8.1 Hz, 1H), 8.50 (s, 1H), 8.48 (s, 1H), 7.86 (dd, J = 8.1, 1.1 Hz, 1H), 7.59 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 6.58 (dd, J = 15.6, 8.9 Hz, 1H), 5.87 (s, 2H), 5.66 (dd, J = 15.6, 1.2 Hz, 1H), 5.07 (t, J = 5.4 Hz, 1H), 4.98 (dd, J = 8.8, 1.2 Hz, 1H), 4.27 (d, J = 5.3 Hz, 2H), 3.86 (s, 3H), 1.78 - 1.68 (m, 1H), 1.11 - 0.99 (m, 2H), 0.90 - 0.78 (m, 2H).623.391Compound 93 1< H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.71 (s, 1H), 8.61 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.41 (dd, J = 7.9, 1.7 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.67 (s, 2H), 4.05 (s, 3H), 3.95 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 2.61 (t, J = 7.0 Hz, 2H), 2.26 - 2.15 (m, 2H), 1.78 - 1.66 (m, 1H), 1.13 - 1.00 (m, 2H), 0.89 - 0.78 (m, 2H).613.392Compound 94 1< H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.94 (t, J = 8.0 Hz, 1H), 8.71 (s, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 5.68 (s, 2H), 3.95 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 2.60 (t, J = 7.0 Hz, 2H), 2.27 - 2.15 (m, 2H), 1.75 - 1.65 (m, 1H), 1.09 - 1.01 (m, 2H), 0.85 - 0.75 (m, 2H).601.293Compound 95 1< H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.30 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.36 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 4.9 Hz, 2H), 7.54 - 7.44 (m, 4H), 7.25 (d, J = 5.1 Hz, 1H), 5.90 (s, 2H), 4.46 - 4.31 (m, 1H), 3.94 (s, 3H), 1.96 - 1.85 (m, 1H), 1.35 (d, J = 6.6 Hz, 6H), 0.49 - 0.39 (m, 2H), 0.14 - 0.06 (m, 2H).584.294Compound 96 1< H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.71 (s, 1H), 8.52 (dd, J = 8.0, 2.3 Hz, 1H), 8.21 (d, J = 12.3 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.82 (ddd, J = 11.0, 7.9, 1.1 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 8.0, 1.8 Hz, 1H), 5.83 (s, 2H), 3.95 (t, J = 6.7 Hz, 2H), 3.87 (s, 3H), 2.60 (t, J = 7.0 Hz, 2H), 2.26 - 2.14 (m, 2H), 1.81 - 1.65 (m, 7H), 1.14 - 0.98 (m, 2H), 0.90 - 0.75 (m, 2H).658.295Compound 97 1< H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.68 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.42 - 7.31 (m, 2H), 6.58 (d, J = 8.6 Hz, 1H), 5.56 (s, 2H), 4.81 - 4.71 (m, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.86 (s, 3H), 3.68 - 3.58 (m, 2H), 3.55 - 3.46 (m, 2H), 2.61 (t, J = 7.0 Hz, 2H), 2.28 - 2.17 (m, 2H), 1.76 - 1.64 (m, 1H), 1.10 - 1.00 (m, 2H), 0.89 - 0.75 (m, 2H).642.296Compound 98 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.71 (s, 1H), 8.61 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.40 (dd, J = 8.0, 1.8 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.67 (s, 2H), 4.47 (t, J = 5.8 Hz, 2H), 3.95 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.04 (t, J = 5.7 Hz, 2H), 2.61 (t, J = 7.0 Hz, 2H), 2.22 (t, J = 6.9 Hz, 2H), 1.75 - 1.66 (m, 1H), 1.10 - 1.02 (m, 2H), 0.89 - 0.76 (m, 2H).642.397Compound 99 1< H NMR (401 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.72 (s, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.37 - 7.29 (m, 2H), 5.80 (s, 2H), 4.47 - 4.34 (m, 1H), 3.92 (t, J = 6.7 Hz, 2H), 3.88 (s, 3H), 3.16 (s, 3H), 2.58 (t, J = 7.0 Hz, 2H), 2.19 (p, J = 6.9 Hz, 2H), 1.75 - 1.66 (m, 1H), 1.11 - 1.01 (m, 8H), 0.89 - 0.81 (m, 2H).717.298Compound 100 1< H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.56 (s, 1H), 8.70 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 1.4 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.26 - 7.20 (m, 2H), 5.81 - 5.63 (m, 2H), 4.22 - 4.07 (m, 1H), 3.86 (s, 3H), 3.72 - 3.57 (m, 1H), 2.78 - 2.69 (m, 1H), 2.47 - 2.39 (m, 1H), 1.88 - 1.76 (m, 1H), 1.74 - 1.61 (m, 1H), 1.19 - 1.10 (m, 3H), 1.10 - 1.01 (m, 2H), 0.91 - 0.80 (m, 2H).689.399Compound 102 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.25 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.54 - 7.50 (m, 3H), 5.96 (s, 2H), 4.89 - 4.85 (m, 1H), 3.72 (s, 3H), 1.19 - 1.17 (m, 2H), 1.06 - 1.03 (m, 2H).584.3100Compound 103 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 9.27 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.29 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.69 (d, J = 1.2 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 5.89 (s, 2H), 4.44 - 4.38 (m, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 1.0 - 0.96 (m, 2H), 0.81 - 0.76 (m, 2H).544.3101Compound 104 1< H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.05 (d,J = 8.0 Hz, 1H), 8.72 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 4 .0Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 4 .0Hz, 1H), 7.31 (dd, J = 8.0, 4.0 Hz, 1H), 5.75 (s, 2H), 3.95 (t, J = 8.0 Hz, 2H), 3.86 (s, 3H), 2.59 (t, J = 8.0 Hz, 2H), 2.25 - 2.15 (m, 2H), 1.76 - 1.67 (m, 1H), 1.08 - 1.03 (m, 2H), 0.84 - 0.78 (m, 2H).651.2102Compound 105 1< H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.72 (s, 1H), 8.64 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 4.0 Hz, 1H), 7.62 - 7.51 (m, 2H), 7.46 - 7.36 (m, 2H), 5.71 (s, 2H), 3.94 (t, J = 8.0 Hz, 2H), 3.87 (s, 3H), 2.60 (t, J = 8.0 Hz, 2H), 2.27 - 2.13 (m, 2H), 1.77 - 1.68 (m, 1H), 1.37 (d, J = 8.0 Hz, 6H), 1.12 - 1.02 (m, 3H), 0.89 - 0.80 (m, 2H),626.2103Compound 109 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.77 (s, 1H), 8.71 (s, 1H), 8.54 (dd, J = 8.0, 2.0 Hz, 1H), 8.18 (d, J = 12.0 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.77 (dd, J = 10.0, 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 5.92 (s, 2H), 4.42 - 4.33 (m, 1H), 3.87 (m, 3H), 2.13 - 1.87 (m, 8H), 1.76 - 1.68 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H), 1.09 - 1.01 (m, 2H), 0.87 - 0.79 (m, 2H).686.2104Compound 111 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (s, 1H), 8.83 (s, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.58 (d,J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.24 (dd, J = 8.0, 1.6 Hz, 1H), 6.10 (d, J = 8.8 Hz, 1H), 5.55 (d, J = 15.6 Hz, 1H), 5.50 (d, J = 15.6 Hz, 1H), 3.99 (s, 3H), 3.97 - 3.91 (m, 5H), 2.59 (t, J = 7.0 Hz, 2H), 2.26 - 2.16 (m, 2H), 1.84 - 1.74 (m, 1H), 1.19 - 1.05 (m, 2H), 0.98 - 0.89 (m, 1H), 0.83 - 0.73 (m, 1H),613.2105Compound 112 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 9.50 (s, 1H), 9.30 (s, 1H), 8.73 (s, 1H), 7.96 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J = 6.8 Hz, 1H), 5.85 (s, 2H), 3.95 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 2.61 (t, J = 6.8 Hz, 2H), 2.26 - 2.15 (m, 2H), 1.80 - 1.71 (m, 1H), 1.11 - 1.04 (m, 2H), 0.89 - 0.80 (m, 2H).584.3106Compound 113 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 9.69 (s, 1H), 9.21 (s, 1H), 8.72 (s, 1H), 7.96 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.33 (dd, J = 8.0, 1.2 Hz, 1H), 5.73 (s, 2H), 3.95 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 2.60 (t, J = 7.0 Hz, 2H), 2.26 - 2.15 (m, 2H),1.76 - 1.67 (m, 1H), 1.09 - 1.02 (m, 2H), 0.85 - 0.76 (m, 2H).584.2107Compound 116 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.73 (s, 1H), 8.35 (dd, J = 5.2, 2.8 Hz, 1H), 8.19 (dd, J = 5.4, 1.8 Hz, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 5.87 (s, 2H), 3.88 (s, 3H), 3.73 (s, 3H), 1.81 - 1.65 (m, 1H), 1.14 - 1.02 (m, 2H), 0.93 - 0.77 (m, 2H).575.2108Compound 117 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.70 (s, 1H), 8.78 (dd, J = 8.6, 2.6 Hz, 1H), 8.74 - 8.68 (m, 2H), 7.90 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 5.77 (s, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 1.77 - 1.68 (m, 1H), 1.10 - 1.02 (m, 2H), 0.88 - 0.80 (m, 2H).575.2109Compound 119 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 8.69 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.45 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 5.90 (s, 2H), 4.10 (t, J = 6.6 Hz, 2H), 3.82 (s, 3H), 2.84 (t, J = 6.8 Hz, 2H), 2.28 - 2.18 (m, 2H), 1.69 - 1.60 (m, 1H), 1.05 - 0.98 (m, 2H), 0.80 - 0.72 (m, 2H).608.2110Compound 121 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 9.02 (d, J = 7.9 Hz, 1H), 8.72 (s, 1H), 8.15 (dd, J = 4.6, 3.2 Hz, 2H), 7.51 (s, 4H), 5.79 (s, 2H), 4.45 - 4.34 (m, 1H), 3.86 (s, 3H), 1.78 - 1.68 (m, 1H), 1.36 (d, J = 6.6 Hz, 6H), 1.09 - 1.02 (m, 2H), 0.86 - 0.77 (m, 2H).610.2111Compound 122 1< HNMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.96 (s, 1H), 8.71 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 5.85 (s, 2H), 3.88 (s, 3H), 3.71 (s, 3H), 1.78 - 1.68 (m, 1H), 1.11 - 1.03 (m, 2H), 0.90 - 0.80 (m, 2H).722.2112Compound 124 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 8.71 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.53 - 8.22 (m, 2H), 7.94 (s, 1H), 7.80 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.92 (t, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.47 - 3.36 (m, 1H), 3.27 - 3.14 (m, 1H), 2.86 - 2.75 (m, 1H), 2.71 - 2.57 (m, 1H), 1.80 - 1.68 (m, 1H), 1.12 - 1.00 (m, 2H), 0.93 - 0.80 (m, 2H).583.3113Compound 125 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 9.06 (d, J = 7.9 Hz, 1H), 8.72 (s, 1H), 8.47 (dd, J = 7.3, 1.1 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.75 - 7.67 (m, 1H), 7.63 - 7.56 (m, 2H), 7.19 (dd, J = 9.3, 6.5 Hz, 1H), 6.93 - 6.85 (m, 1H), 5.82 (s, 2H), 3.87 (s, 3H), 1.80 - 1.69 (m, 1H), 1.10 - 1.02 (m, 2H), 0.88 - 0.79 (m, 2H).661.5114Compound 126 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.72 (s, 1H), 8.59 (d, 7.8 Hz, 2H), 8.47 (d, J = 7.4 Hz, 1H), 7.87 (dd, J = 8.3, 1.2 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.71 (dd, J = 9.3, 1.2 Hz, 1H), 7.65 7.57 (m, 2H), 7.19 (dd, J = 9.3, 6.5 Hz, 1H), 6.96 - 6.83 (m, 1H), 5.88 (s, 2H), 3.88 (s, 3H), 1.79 - 1.70 (m, 1H), 1.10 - 1.03 (m, 2H), 0.90 - 0.81 (m, 2H).617.5115Compound 127 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 9.05 (d, J = 8.0 Hz, 1H), 8.72 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 4 .0Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 4 .0Hz, 1H), 7.31 (dd, J = 8.0, 4.0 Hz, 1H), 5.75 (s, 2H), 3.95 (t, J = 8.0 Hz, 2H), 3.86 (s, 3H), 2.59 (t, J = 8.0 Hz, 2H), 2.25 - 2.15 (m, 2H), 1.76 - 1.67 (m, 1H), 1.08 - 1.03 (m, 2H), 0.84 - 0.78 (m, 2H).651.2116Compound 128 1< H NMR (400 MHz, DMSO--d 6 ) δ 9.62 (s, 1H), 8.69 (s, 1H), 8.64 (d, J = 8.0 Hz, 1H), 7.95 (q, J = 4.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.25 (dd, J = 8.0, 4.0 Hz, 1H), 5.72 (s, 2H), 3.95 (t, J = 8.0 Hz, 2H), 3.84 (s, 3H), 2.68 (s, 3H), 2.59 (d, J =8.0 Hz, 2H), 2.25 - 2.15 (m, 2H), 1.72 - 1.64 (m, 1H), 1.06 - 0.99 (m, 2H), 0.83 - 0.75 (m, 2H).597.6117Compound 129 1< H NMR (400 MHz, Methanol-d 4 ) δ 9.66 (s, 1H), 9.18 (s, 1H), 8.64 (s, 1H), 8.52 (dd, J = 8.1, 0.7 Hz, 1H), 8.37 (dd, J = 5.2, 1.6 Hz, 1H), 8.20 (dd, J = 1.4, 0.7 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.77 (dd, J = 8.1, 1.4 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 5.92 (s, 2H), 3.94 (s, 3H), 1.81 - 1.72 (m, 1H), 1.16 (m, 2H), 0.92 - 0.86 (m, 2H).618.5118Compound 130 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 9.50 (s, 1H), 9.30 (s, 1H), 8.73 (s, 1H), 7.96 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J = 6.8 Hz, 1H), 5.85 (s, 2H), 3.95 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 2.61 (t, J = 6.8 Hz, 2H), 2.26 - 2.15 (m, 2H), 1.80 - 1.71 (m, 1H), 1.11 - 1.04 (m, 2H), 0.89 - 0.80 (m, 2H).584.3119Compound 132 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.72 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 8.53 (d, J = 1.1 Hz, 1H), 7.99 (t, J = 1.4 Hz, 1H), 7.86 (dd, J = 8.1, 1.3 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.40 (dd, J = 8.2, 1.8 Hz, 1H), 5.91 - 5.77 (m, 2H), 4.65 (dd, 1H), 3.86 (s, 3H), 3.82 - 3.71 (m, 1H), 3.27 (t, J = 12.3 Hz, 1H), 3.01 - 2.86 (m, 1H), 1.76 - 1.66 (m, 1H), 1.11 - 1.02 (m, 2H), 0.91 - 0.80 (m, 2H).655.2120Compound 134 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.51 (s, 1H), 8.71 (s, 1H), 8.57 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.40 (dd, J = 7.9, 1.7 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 5.65 (s, 2H), 5.46 (h, J = 6.1 Hz, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H), 2.61 (t, J = 7.0 Hz, 2H), 2.26 - 2.15 (m, 2H), 1.77 - 1.66 (m, 1H), 1.38 (d, J = 6.1 Hz, 6H), 1.11 -. 1.03 (m, 2H), 0.89 - 0.80 (m, 2H).641.2121Compound 135 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.36 (s, 1H), 8.69 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.95 (q, J = 1.3 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.35 (dd, J = 8.0, 1.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.59 (s, 2H), 3.95 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.76 (dd, J = 5.7, 3.6 Hz, 4H), 3.68 (t, J = 4.7 Hz, 4H), 2.60 (t, J = 7.0 Hz, 2H), 2.21 (p, J = 6.9 Hz, 2H), 1.71 (m, 1H), 1.04 (m, 2H), 0.83 (m, 2H).668.3122Compound 136 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 8.69 (s, 1H), 8.35 (dd, J = 8.5, 1.1 Hz, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 8.0, 1.7 Hz, 1H), 6.44 (dd, J = 8.5, 0.9 Hz, 1H), 5.74 (d, J = 6.7 Hz, 1H), 5.56 (s, 2H), 4.69 - 4.59 (m, 1H), 4.38 - 4.29 (m, 2H), 3.96 (t, J = 6.8 Hz, 2H), 3.88 - 3.81 (m, 5H), 2.61 (t, J = 7.0 Hz, 2H), 2.22 (m, 2H), 1.70 (m, 1H), 1.04 (m, 2H), 0.82 (m, 2H).654.3123Compound 137 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 8.69 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.98 - 7.93 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 8.0, 1.8 Hz, 1H), 6.46 (d, J = 8.5 Hz, 1H), 5.57 (s, 2H), 4.44 - 4.35 (m, 1H), 4.32 (dd, J = 9.1, 6.3 Hz, 2H), 3.99 - 3.89 (m, 4H), 3.85 (s, 3H), 3.29 (s, 3H), 2.61 (t, J = 7.0 Hz, 2H), 2.27 - 2.16 (m, 2H), 1.75 - 1.64 (m, 1H), 1.08 - 1.00 (m, 2H), 0.86 - 0.77 (m, 2H).668.3124Compound 140 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 9.02 (d, J = 7.9 Hz, 1H), 8.71 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 1.3 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.32 - 7.25 (m, 1H), 5.75 (s, 2H), 3.96 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 2.60 (t, J = 7.0 Hz, 2H), 2.26 - 2.15 (m, 2H), 1.77 - 1.66 (m, 1H), 1.09 - 1.01 (m, 2H), 0.84 - 0.75 (m, 2H).608.3125Compound 141 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.77 (s, 1H), 8.71 (s, 1H), 8.54 (dd, J = 8.0, 2.3 Hz, 1H), 8.25 - 8.15 (m, 2H), 7.78 (m, 1H), 7.53 - 7.39 (m, 2H), 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 5.93 (s, 2H), 4.15 - 3.99 (m, 1H), 3.86 (s, 3H), 2.13 - 1.87 (m, 8H), 1.80 - 1.63 (m, 1H), 1.31 (d, J = 6.6 Hz, 6H), 1.09 - 1.00 (m, 2H), 0.88 - 0.79 (m, 2H).704.2126Compound 142 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 8.71 (s, 1H), 8.53 (dd, J = 7.9, 2.3 Hz, 1H), 8.15 (d, J = 12.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 3H), 7.40 (d, J = 8.1 Hz, 2H), 5.87 (s, 2H), 4.25 (t, J = 7.2 Hz, 2H), 3.87 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.09 - 1.90 (m, 8H), 1.77 - 1.67 (m, 1H), 1.09 - 1.02 (m, 2H), 0.88 - 0.78 (m, 2H).684.2127Compound 146 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.70 (s, 1H), 8.78 (dd, J = 8.6, 2.8 Hz, 1H), 8.70 (d, J = 3.8 Hz, 2H), 7.95 (d, J = 1. 5 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 7.9, 1.8 Hz, 1H), 5.73 (s, 2H), 3.95 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 2.60 (t, J = 7.0 Hz, 2H), 2.26 - 2.14 (m, 2H), 1.77 - 1.66 (m, 1H), 1.09 - 1.01 (m, 2H), 0.86 - 0.77 (m, 2H).601.2128Compound 150 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.32 (s, 1H), 8.73 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.48 (d, J = 7.2 Hz, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 9.3, 6.5 Hz, 1H), 6.88 (t, J = 6.9 Hz, 1H), 5.92 (s, 2H), 3.89 (s, 3H), 1.75 (m, 1H), 1.12 - 1.04 (m, 2H), 0.94 - 0.81 (m, 2H).593.2129Compound 151 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 9.30 (s, 1H), 8.72 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.60 - 7.51 (m, 4H), 5.87 (s, 2H), 3.88 (s, 3H), 3.53 (s, 3H), 2.33 (d, J = 1.8 Hz, 3H), 1.79 - 1.68 (m, 1H), 1.11 - 1.03 (m, 2H), 0.91 - 0.82 (m, 2H).571.5130Compound 152 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.29 (s, 1H), 8.72 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 5.89 (s, 2H), 3.88 (s, 3H), 3.62 (s, 3H), 1.80 - 1.69 (m, 1H), 1.11 - 1.03 (m, 2H), 0.92 - 0.82 (m, 2H),635.4131Compound 153 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.29 (s, 1H), 8.72 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.36 (t, J = 6.6 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 5.89 (s, 2H), 3.88 (s, 3H), 3.61 (s, 3H), 1.79 - 1.69 (m, 1H), 1.11 - 1.03 (m, 2H), 0.91 - 0.81 (m, 2H).63 5.4132Compound 154 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.71 (s, 1H), 8.51 (dd, J = 7.9, 2.2 Hz, 1H), 8.15 (d, J = 11.2 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.76 (m, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.25 (dd, J = 8.0, 1.8 Hz, 1H), 5.83 (s, 2H), 3.94 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H), 2.63 - 2.52 (m, 2H), 2.25 - 2.14 (m, 2H), 2.14 - 1.90 (m, 4H), 1.76 - 1.65 (m, 1H), 1.10 - 1.02 (m, 2H), 0.99 - 0.87 (m, 6H), 0.87 - 0.78 (m, 2H),686.6133Compound 155 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 9.48 (s, 1H), 8.77 - 8.71 (m, 2H), 8.59 (d, J = 5.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.60 - 7.53 (m, 2H), 5.93 (s, 2H), 3.88 (s, 3H), 3.67 (s, 3H), 1.80 - 1.69 (m, 1H), 1.11 - 1.03 (m, 2H), 0.89 - 0.80 (m, 2H).575.5134Compound 157 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.72 (s, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.04 - 7.92 (m, 2H), 7.79 - 7.67 (m, 1H), 7.61 - 7.49 (m, 3H), 7.39 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 - 7.25 (m, 1H), 7.16 - 7.02 (m, 1H), 5.80 (s, 2H), 3.87 (s, 3H), 3.27 (s, 2H), 2.75 - 2.54 (m, 2H), 2.20 (m, 3H), 2.05 - 1.95 (m, 2H), 1.75 - 1.64 (m, 1H), 1.13 - 1.03 (m, 2H), 0.89 - 0.79 (m, 2H).701.6135Compound 158 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.08 (s, 1H), 9.52 (s, 1H), 8.72 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 7.9, 1.7 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.63 (s, 2H), 4.96 (s, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.88 (s, 3H), 3.85 (q, J = 3.3, 2.7 Hz, 4H), 2.63 (t, J = 7.0 Hz, 2H), 2.27 - 2.15 (m, 2H), 1.78 - 1.67 (m, 1H), 1.12 - 1.04 (m, 2H), 0.90 - 0.81 (m, 2H).706.2136Compound 159 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.68 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 5.64 (s, 2H), 3.95 (t, J = 6.7 Hz, 2H), 3.83 (s, 3H), 2.60 (t, J = 7.0 Hz, 2H), 2.25 - 2.14 (m, 2H), 1.70 - 1.62 (m, 1H), 1.02 (s, 2H), 0.81 - 0.74 (m, 2H).600.2137Compound 160 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.80 (s, 1H), 8.71 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.00 (dd, J = 8.2, 1.6 Hz, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.0, 1.8 Hz, 1H), 5.93 - 5.79 (m, 2H), 4.38 (s, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.86 (s, 3H), 3.16 (d, J = 0.9 Hz, 3H), 2.60 (t, J = 7.0 Hz, 2H), 2.26 - 2.15 (m, 2H), 1.78 - 1.67 (m, 1H), 1.09 - 101 (m, 2H), 0.88 - 0.77 (m, 2H).660.2138Compound 161 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.71 (s, 1H), 8.59 (d, J = 8.1 Hz, 1H), 8.50 (d, J = 1.3 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.86 (dd, J = 8.1, 1.3 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.0, 1.8 Hz, 1H), 5.80 (s, 2H), 3.95 (t, J = 6.8 Hz, 2H), 2.64 - 2.52 (m, 2H), 2.26 - 2.14 (m, 2H), 1.77 - 1.66 (m, 1H), 1.10 - 1.02 (m, 2H), 0.87 - 0.77 (m, 2H),610.2139Compound 163 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.25 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.35 (dd, J = 5.1, 1.1 Hz, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.57 - 7.48 (m, 3H), 5.96 (s, 2H), 4.92 - 4.82 (m, 1H), 3.72 (s, 3H), 1.22 - 1.14 (m, 2H), 1.13 - 0.99 (m, 2H).583.0140Compound 164 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 8.72 (s, 1H), 8.59-8.55 (t, J = 13.6 Hz, 1H), 7.87-7.85 (d, J = 8.0Hz, 1H), 7.60 - 7.52 (m, 4H), 5.84 (s, 2H), 3.88 (s, 1H), 3.65 (s, 3H), 1.79-1.73 (m, 2H), 1.07-1.02(m, 4H), 0.86-0.84(m,2H), 0.71-0.70(m,2H).621.6 Example 141: 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo 1-2-yl)benzyl)-2-methyl-2,8-dihydropyrazolo[4',3':4,5]pyrrolo [2,3-d]pyrimidine

[0668] Operation steps:

[0669] Step A: 3-Chloro-1H-pyrazole (5 g, 49.0 mmol) was dissolved in N,N-dimethylformamide (50 mL) at 0°C. Subsequently, N-iodosuccinimide (14.3 g, 63.7 mmol) was slowly added to the above solution. The reaction system was then stirred at room temperature for 2 hours.

[0670] After the disappearance of raw materials as monitored by LCMS, ice water (200 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and washed with saturated saline (35 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11 g of 3-chloro-4-iodo-1H-pyrazole.

[0671] MS(ESI) M / Z: 229.0 [M+H] +< .

[0672] Step B: 3-Chloro-4-iodo-1H-pyrazole (3.5 g, 15.35 mmol) was dissolved in dry tetrahydrofuran (77 mL) at 0°C under nitrogen protection. Subsequently, sodium hydride (content 60%) (1.2 g, 30.70 mmol) was slowly added to the above solution, and the resultant was stirred for 30 minutes. Then, methyl iodide (4.3 g, 30.70 mmol) was slowly added dropwise, and the mixture was heated to room temperature and stirred for 1 hour.

[0673] After the disappearance of raw materials as monitored by LCMS, ice water (150 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and then washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2 g of 3-chloro-4-iodo-1-methyl-1H-pyrazole.

[0674] MS(ESI) M / Z: 243.0 [M+H] +< .

[0675] 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.93 (s, 1H), 3.81 (s, 3H).

[0676] Step C: 3-Chloro-4-iodo-1-methyl-1H-pyrazole (1.6 g, 6.61 mmol) was dissolved in dry tetrahydrofuran (33 mL) at room temperature. Subsequently, 2 M isopropyl magnesium chloride (10.5 mL, 21.02 mmol) solution was slowly added dropwise into the above solution, and the resultant was stirred for 1 hour. Then, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.43 mg, 28.03 mmol) was added, and stirring was continued for 1 hour.

[0677] After the disappearance of raw materials as monitored by LCMS, water (150 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and then washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2 g of 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole.

[0678] MS (ESI) M / Z: 243.2 [M+H] +< .

[0679] Step D: 3-Chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 8.23 mmol), 5-bromo-2-chloro-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.5 g, 4.12 mmol) and sodium carbonate (0.87 g, 8.23 mmol) were dissolved in 1,4-dioxane / water (20 mL / 2.2 mL) at room temperature. Subsequently, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.33 g, 0.41 mmol) was added to the above solution, and the reaction system was evacuated to remove air and purged with nitrogen for 3 times, and the reaction system was stirred at 90°C for 16 hours.

[0680] After the disappearance of raw materials as monitored by LCMS, ice water (50 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and then washed with saturated sodium chloride aqueous solution (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 780 mg of 2-chloro-5-(3-chloro-1-methyl-1H-pyrazol-4-yl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine.

[0681] MS (ESI) M / Z: 394.2 [M+H] +< .

[0682] Step E: 2-Chloro-5-(3-chloro-1-methyl-1H-pyrazol-4-yl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (780 mg, 1.98 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boric acid (386 mg, 1.98 mmol) and cesium carbonate (1.29 g, 3.96 mmol) were dissolved in 1,4-dioxane / water (10 mL / 1.7 mL) at room temperature. Subsequently, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]pall adium(II) (312 mg, 0.40 mmol) was added to the above solution, and the reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C under microwave for three hours.

[0683] After the disappearance of raw materials as monitored by LCMS, ice water (50 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and then washed with saturated sodium chloride aqueous solution (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 650 mg of 5-(3-chloro-1-methyl-1H-pyrazol-4-yl)-4'-cyclopropyl-N-(2,4-dimethoxybenzyl)-6'-methoxy-[2,5'-bipyrimidine]-4-amine.

[0684] MS (ESI) M / Z: 508.2 [M+H] +< .

[0685] Step F: 5-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-4'-cyclopropyl-N-(2,4-dimethoxybenzyl)-6'-methoxy-[2,5' -bipyrimidine]-4-amine (650 mg, 1.28 mmol), N,N'-dimethyl ethylenediamine (68 mg, 0.77 mmol) and potassium carbonate (353 mg, 2.56 mmol) were dissolved in acetonitrile (6.4 mL) at room temperature. Subsequently, cuprous iodide (73 mg, 0.38 mmol) was added, and the reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 120°C for 16 hours.

[0686] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 180 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(2,4-dimethoxybenzyl)-2-methyl-2,8-dihydropyraz olo[4',3"4,5]pyrrolo[2,3-d]pyrimidine.

[0687] MS (ESI) M / Z: 472.2 [M+H] +< .

[0688] Step G: At room temperature and under nitrogen protection, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(2,4-dimethoxybenzyl)-2-methyl-2,8-dihydropyraz olo[4',3':4,5]pyrrolo[2,3-d]pyrimidine (180 mg, 0.38 mmol) was dissolved in trifluoroacetic acid (8 mL). Then, the reaction system was stirred at 85°C for 16 hours.

[0689] After the disappearance of raw materials as monitored by LCMS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 120 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-2,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d] pyrimidine.

[0690] MS (ESI) M / Z: 322.2 [M+H] +< .

[0691] Step H: 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-2,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d ]pyrimidine (100 mg, 0.31 mmol) was dissolved in dry N,N-dimethylformamide (1.5 mL) at 0°C under nitrogen protection. Subsequently, sodium hydride (content 60%) (50 mg, 1.24 mmol) was slowly added to the above solution, and the resultant was stirred for 0.5 hour. Then, 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (162 mg, 0.47 mmol) was added. The reaction system was heated to 50°C and stirred for 16 hours.

[0692] After the disappearance of raw materials as monitored by LCMS, ice water (30 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined. The combined organic phase was then washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. 25.98 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine (compound 88) was obtained.

[0693] MS (ESI) M / Z: 588.3 [M+H] +< .

[0694] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.51 (s, 2H), 4.45-4.36 (m, 1H), 4.05 (s, 3H), 3.85 (s, 3H), 1.76-1.67 (m, 1H), 1.37 (d, J = 6.4 Hz, 6H), 1.08-1.00 (m, 2H), 0.87-0.80 (m, 2H).Example 142: 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo 1-2-yl)benzyl)-1,8-dihydropyrazole[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0695] Operation steps:

[0696] Step A: 3-Chloro-1H-pyrazole (5 g, 49.02 mmol) was dissolved in N,N-dimethylformamide (50 mL) at 0°C. Subsequently, N-iodosuccinimide (14.3 g, 63.73 mmol) was slowly added to the above solution. The reaction system was then stirred at room temperature for 2 hours.

[0697] After the disappearance of raw materials as monitored by LCMS, ice water (200 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and then washed with saturated saline (35 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11 g of 3-chloro-4-iodo-1H-pyrazole.

[0698] MS(ESI) M / Z: 229.0 [M+H] +< .

[0699] Step B: 3-Chloro-4-iodo-1H-pyrazole (4 g, 17.54 mmol) was dissolved in N,N-dimethylformamide (88 mL) under nitrogen protection at room temperature. Subsequently, sodium hydride (1.05 g, 26.32 mmol) was added to the above solution under ice-water bath, and the resultant was stirred for 30 minutes. Then 2-(trimethylsilyl)ethoxymethyl chloride (4.4 g, 26.32 mmol) was slowly added, and the mixture was heated to room temperature and stirred for 1 hour.

[0700] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding into ice water (500 mL). The mixed solution was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (60 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5 g of 3-chloro-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole.

[0701] MS (ESI) M / Z: 359.0 [M+H] +< .

[0702] Step C: 3-Chloro-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (5 g, 13.97 mmol) was dissolved in dry tetrahydrofuran (70 mL) at room temperature. Subsequently, 2 M isopropyl magnesium chloride (22.5 mL, 44.70 mmol) was added to the above solution, and the resultant was stirred for 1 hour. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.5 g, 60.07 mmol) was slowly added dropwise, and stirring was continued for 1 hour.

[0703] After the disappearance of raw materials as monitored by LCMS, the reaction solution was quenched by adding into ice water (100 mL). The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and then washed with saturated saline (60 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4 g of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole.

[0704] MS (ESI) M / Z: 359.2 [M+H] +< .

[0705] Step D: 3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -pyrazole (4 g, 11.17), (5-bromo-2-chloro-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (2 g, 5.59 mmol), sodium carbonate (1.18 g, 11.17 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (915 mg, 1.12 mmol) were dissolved in 1,4-dioxane / water (54 mL / 6 mL) at room temperature. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and the reaction system was stirred at 100°C for 2 hours.

[0706] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3 g of 2-chloro-5-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-N-(2,4-dimethoxyben zyl)pyrimidin-4-amine.

[0707] MS (ESI) M / Z: 510.2 [M+H] +< .

[0708] Step E: 2-Chloro-5-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-N-(2,4-dimethoxyben zyl)pyrimidin-4-amine (3 g, 5.89 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boric acid (2.3 g, 11.78 mmol), cesium carbonate (2.9 g, 8.84 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-bipheny)]pall adium(II) (2.3 g, 2.95 mmol) were dissolved in 1,4-dioxane / water (54 mL / 9 mL) at room temperature. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and the reaction system was stirred at 130°C for 16 hours.

[0709] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 240 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(2,4-dimethoxybenzyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine.

[0710] MS (ESI) M / Z: 588.2 [M+H] +< .

[0711] Step F: At room temperature, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(2,4-dimethoxybenzyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine (200 mg, 0.34 mmol) was dissolved in trifluoroacetic acid (3 mL). Then, the reaction system was stirred at 85°C for 5 hours.

[0712] After the disappearance of raw materials as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 70 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidin e.

[0713] MS (ESI) M / Z: 308.2 [M+H] +< .

[0714] Step G: 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidi ne (25 mg, 0.08 mmol), 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (28 mg, 0.08 mmol) and potassium carbonate (23 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature. The reaction system was then stirred at 50°C for 2 hours.

[0715] After the disappearance of raw materials as monitored by LCMS, ice water (30 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and then washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 3.60 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine was obtained.

[0716] MS (ESI) M / Z: 574.2 [M+H] +< .

[0717] 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.17 (s, 1H), 9.13 (s, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.53-7.46 (m, 4H), 5.53 (s, 2H), 4.45-4.34 (m, 1H), 3.86 (s, 3H), 1.76-1.66 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H), 1.07-1.00 (m, 2H), 0.91-0.80 (m, 2H).Example 143: 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazo 1-2-yl)benzyl)-1-methyl-1,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine

[0718] Operation steps:

[0719] Step A: 3-Chloro-4-iodo-1H-pyrazole (112 g, 491 mmol) was dissolved in dry tetrahydrofuran (1.4 L) at 0°C under nitrogen protection. Subsequently, sodium hydride (42 g, 1.05 mol) was slowly added to the above solution, and the resultant was stirred for 30 minutes. Then methyl iodide (104 g, 736 mmol) was added dropwise, and the mixture was heated to room temperature and stirred for 4 hours.

[0720] After the disappearance of raw materials as monitored by LCMS, ice water (5 L) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (1000 mL × 3 times), and the organic phases were combined and then washed with saturated saline (600 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 23 g of 5-chloro-4-iodo-1-methyl-1H-pyrazole.

[0721] MS (ESI) M / Z: 243.0 [M+H] +< .

[0722] 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.64 (s, 1H), 3.87 (s, 3H).

[0723] Step B: 5-Chloro-4-iodo-1-methyl-1H-pyrazole (3 g, 12.39 mmol) was dissolved in dry tetrahydrofuran (62 mL) at room temperature. Subsequently, 2 M isopropyl magnesium chloride solution (19.7 mL, 39.4 mmol) was added dropwise to the above solution and stirred for 1 hour. Then 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.72 g, 52.5 mmol) was added, and stirring was continued for 1 hour.

[0724] After the disappearance of raw materials as monitored by LCMS, water (150 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and then washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.1 g of 5-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0725] MS (ESI) M / Z: 243.2 [M+H] +< .

[0726] Step C: 5-Chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 8.23 mmol), 5-bromo-2-chloro-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.5 g, 4.12 mmol) and sodium carbonate (0.87 g, 8.23 mmol) were dissolved in 1,4-dioxane / water (20 mL / 2.2 mL) at room temperature. Subsequently, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.33 g, 0.41 mmol) was added to the above solution. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C for 16 hours.

[0727] After the disappearance of raw materials as monitored by LCMS, ice water (50 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and then washed with saturated sodium chloride aqueous solution (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.8 g of 2-chloro-5-(5-chloro-1-methyl-1H-pyrazol-4-yl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine.

[0728] MS (ESI) M / Z: 394.2 [M+H] +< .

[0729] Step D: 2-Chloro-5-(5-chloro-1-methyl-1H-pyrazol-4-yl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.8 g, 4.57 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boric acid (891 mg, 4.57 mmol) and cesium carbonate (3 g, 9.14 mmol) were dissolved in 1,4-dioxane / water (23 mL / 2.3 mL) at room temperature. Subsequently, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]p alladium(II) (644 mg, 0.91 mmol) was added to the above solution. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 90°C under microwave for 16 hours.

[0730] After the disappearance of raw materials as monitored by LCMS, ice water (150 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated sodium chloride aqueous solution (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 800 mg of 5-(5-chloro-1-methyl-1H-pyrazol-4-yl)-4'-cyclopropyl-N-(2,4-dimethoxybenzyl)-6'-methoxy-[2,5 '-bipyrimidine]-4-amine.

[0731] MS (ESI) M / Z: 508.8 [M+H] +< .

[0732] Step E: 5-(5-Chloro-1-methyl-1H-pyrazol-4-yl)-4'-cyclopropyl-N-(2,4-dimethoxybenzyl)-6'-methoxy-[2,5 '-bipyrimidine]-4-amine (800 mg, 1.58 mmol), N,N'-dimethyl ethylenediamine (278 mg, 3.16 mmol) and potassium carbonate (404 mg, 3.16 mmol) were dissolved in N,N-dimethylformamide (8 mL) at room temperature. Subsequently, cuprous iodide (300 mg, 1.58 mmol) was added. The reaction system was evacuated to remove air and purged with nitrogen for 3 times, and then stirred at 120°C for 16 hours.

[0733] After the disappearance of raw materials as monitored by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 520 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(2,4-dimethoxybenzyl)-1-methyl-1,8-dihydropyraz olo[4',3':4,5]pyrrolo[2,3-d]pyrimidine.

[0734] MS (ESI) M / Z: 472.2 [M+H] +< .

[0735] Step F: At room temperature and under nitrogen protection, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(2,4-dimethoxybenzyl)-1-methyl-1,8-dihydropyraz olo[4',3':4,5]pyrrolo[2,3-d]pyrimidine (520 mg, 1.1 mmol) was dissolved in trifluoroacetic acid (6 mL). Then, the reaction system was stirred at 85°C for 8 hours.

[0736] After the disappearance of raw materials as monitored by LCMS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 250 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d] pyrimidine.

[0737] MS (ESI) M / Z: 322.2 [M+H] +< .

[0738] Step G: 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,8-dihydropyrazolo[4°,3 7< :4,5|pyrrolo[2,3-d]pyrimidine (50 mg, 0.16 mmol) was dissolved in dry N,N-dimethylformamide (1.0 mL) at 0°C under nitrogen protection. Subsequently, sodium hydride (25 mg, 0.62 mmol) was added to the above solution, and the resultant was stirred for 20 minutes. Then, 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (60 mg, 0.17 mmol) was added, and the mixture was heated to room temperature and stirred for 1 hour.

[0739] After the disappearance of raw materials as monitored by LCMS, ice water (50 mL) was added to the reaction solution for quenching. The mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated saline (20 mL × 2 times). The resultant was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The purification conditions are as follows: preparative column: YMC-AcTus Triart C18 20.0 mm× 150 mm; mobile phase: water (containing 0.1% ammonium bicarbonate) and acetonitrile. 22.69 mg of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1-methyl-1,8-dihydropyrazolo[4',3':4,5]pyrrolo[2,3-d]pyrimidine was obtained.

[0740] MS (ESI) M / Z: 588.2 [M+H] +< .

[0741] 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.22 (s, 1H), 8.67 (s, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.95 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 5.85 (s, 2H), 4.49-4.33 (m, 1H), 3.97 (s, 3H), 3.85 (s, 3H), 1.74-1.65 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H), 1.06-0.99 (m, 2H), 0.86-0.78 (m, 2H).Examples 144 to 166

[0742] Target compounds in the following Table 2 were prepared by referring to the synthesis method of Example 142 above: Table 2Example Compound Structural formula 1< HNMRMS (ESI)M / Z:[M+H]144Compound 101 1< H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.28 (d, J = 7.9 Hz, 1H), 5.47 (s, 2H), 4.04 (s, 3H), 3.96 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 2.61 (t, J = 7.0 Hz, 2H), 2.28 - 2.15 (m, 2H), 1.76 - 1.65 (m, 1H), 1.09 - 0.99 (m, 2H), 0.89 - 0.77 (m, 2H).586.3145Compound 107 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (s, 1H), 8.68 (s, 1H), 8.27 (s, 1H), 8.23 (d, J = 1.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.38 (dd, J = 10.4, 1.2 Hz, 1H), 7.27 (dd, J = 7.8, 1.4 Hz, 1H), 5.54 (s, 2H), 4.14 - 4.08 (m, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 1.78 - 1.68 (m, 1H), 1.33 (d, J= 6.4 Hz, 6H), 1.08 - 1.00 (m, 2H), 0.89 - 0.78 (m, 2H).606.2146Compound 108 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.50 (s, 2H), 4.05 (s, 3H), 3.86 (s, 3H), 3.73 (s, 3H), 1.76 - 1.68 (m, 1H), 1.08 - 1.01 (m, 2H), 0.88 - 0.81 (m, 2H).560.2147Compound 110 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.51 (s, 2H), 4.45 - 4.35 (m, 1H), 3.86 (s, 3H), 1.76 - 1.68 (m, 1H), 1.37 (d, J = 6.4 Hz, 6H), 1.07 - 1.01 (m, 2H), 0.87 - 0.80 (m, 2H).591.3148Compound 114 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.68 (s, 1H), 8.25 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 5.47 (s, 2H), 4.27 (t, J = 7.0 Hz, 2H), 4.04 (s, 3H), 3.86 (s, 3H), 2.92 (t, J = 6.8 Hz, 2H), 2.68 - 2.57 (m, 2H), 1.76 - 1.68 (m, 1H), 1.08 - 1.01 (m, 2H), 0.88 - 0.81 (m, 2H).586.2149Compound 115 1< H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.68 (s, 1H), 8.28 (s, 1H), 8.05 (d, J = 1.2 Hz, 1H), 7.32 - 7.24 (m, 2H), 5.55 (s, 2H), 4.06 (s, 3H), 3.85 (s, 3H), 3.54 (s, 3H), 1.78 - 1.70 (m, 1H), 1.08 - 1.02 (m, 2H), 0.89 - 0.82 (m, 2H).596.2150Compound 118 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (s, 1H), 8.68 (s, 1H), 8.27 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.37 (dd, J = 11.0, 1.0 Hz, 1H), 7.27 (dd, J = 8.0, 1.2 Hz, 1H), 5.53 (s, 2H), 4.05 (s, 3H), 3.85 (s, 3H), 3.56 (d, J = 0.8 Hz, 3H), 1.80 - 1.66 (m, 1H), 1.09 - 0.99 (m, 2H), 0.90 - 0.79 (m, 2H).578.2151Compound 120 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.68 (s, 1H), 8.25 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 5.49 (s, 2H), 4.09 - 3.98 (m, 5H), 3.86 (s, 3H), 2.88 (brs, 2H), 1.87 - 1.76 (m, 4H), 1.74 - 1.68 (m, 1H), 1.08 - 1.01 (m, 2H), 0.88 - 0.81 (m, 2H).600.2152Compound 123 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.21 (s, 1H), 8.68 (s, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.80 (s, 2H), 4.01- 3.92 (m, 5H), 3.85 (s, 3H), 2.62 (t, J = 6.8 Hz, 2H), 2.26 - 2.16 (m, 2H), 1.74 - 1.65 (m, 1H), 1.07 - 1.01 (m, 2H), 0.86 - 0.79 (m, 2H).586.2153Compound 131 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.66 - 7.60 (m, 2H), 7.48 - 7.42 (m, 2H), 5.49 (s, 2H), 4.05 (s, 3H), 3.86 (s, 3H), 2.61 (s, 3H), 1.77 - 1.66 (m, 1H), 1.08 - 0.96 (m, 2H), 0.88 - 0.79 (m, 2H).577.4154Compound 133 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.40 - 7.33 (m, 1H), 5.60 - 5.38 (m, 2H), 4.65 (dd, J = 15.0, 6.5 Hz, 1H), 4.04 (s, 3H), 3.84 (s, 3H), 3.79 (dd, J = 14.7, 11.3 Hz, 1H), 3.26 (t, J = 12.4 Hz, 1H), 3.01 - 2.86 (m, 1H), 1.75 - 1.64 (m, 1H), 1.08 - 0.99 (m, 2H), 0.88 - 0.78 (m, 2H),634.3155Compound 138 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.96 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.24 (dd,J = 8.0, 1.7 Hz, 1H), 5.50 (s, 2H), 4.21 - 4.11 (m, 1H), 4.05 (s, 3H), 3.84 (s, 3H), 3.72 - 3.59 (m, 1H), 2.79 - 2.66 (m, 1H), 2.50 - 2.36 (m, 1H), 1.87 - 1.75 (m, 1H), 1.73 - 1.62 (m, 1H), 1.11 (d, J = 6.9 Hz, 3H), 1.08 - 1.00 (m, 2H), 087 - 0.78(m, 2H).600.3156Compound 139 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.68 (s, 1H), 8.25 (s, 1H), 7.72 - 7.65 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 5.50 (s, 2H), 4.98 - 4.92 (m, 2H), 4.15 (t, J = 5.1 Hz, 2H), 4.04 (s, 3H), 3.92 (t,J = 5.0 Hz, 2H), 3.86 (s, 3H), 1.78 - 1.67 (m, 1H), 1.09 - 1.00 (m, 2H), 0.90 - 0.81 (m, 2H).602.2157Compound 143 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.64 (t,.J = 7.9 Hz, 1H), 7.34 (dd, J = 11.4, 1.7 Hz, 1H), 7.26 (dd,J = 8.0, 1.7 Hz, 1H), 5.51 (s, 2H), 4.05 (s, 3H), 4.04 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.99 - 2.90 (m, 2H), 2.64 - 2.52 (m, 2H), 1.78 - 1.68 (m, 1H), 1.09 - 1.01 (m, 2H), 0.90 - 0.81 (m, 2H).604.0158Compound 144 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.16 (s, 1H), 8.68 (s, 1H), 8.27 (s, 1H), 7.24 (d, J = 8.5 Hz, 2H), 5.53 (s, 2H), 4.06 (s, 3H), 3.93 (t, J = 7.2 Hz, 2H), 3.85 (s, 3H), 2.97 (t, J = 7.0 Hz, 2H), 2.59 (t, J = 7.1 Hz, 2H), 1.80 - 1.69 (m, 1H), 1.09 - 1.01 (m, 2H), 0.90 - 0.81 (m, 2H).621.8159Compound 145 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (s, 1H), 8.68 (s, 1H), 8.30 - 8.20 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.38 (dd, J = 10.7, 1.6 Hz, 1H), 7.26 (dd, J = 7.9, 1.6 Hz, 1H), 5.54 (s, 2H), 4.15 - 4.04 (m, 1H), 3.85 (s, 3H), 1.78 - 1.67 (m, 1H), 1.32 (d, J = 6.6 Hz, 6H), 1.08 - 1.00 (m, 2H), 0.88 - 0.79 (m, 2H).609.3160Compound 147 1< H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.75 (s, 1H), 8.70 (s, 1H), 7.81 - 7.73 (m, 2H), 7.65 - 7.57 (m, 2H), 7.30 (q, J = 1.2 Hz, 1H), 5.58 (s, 2H), 3.96 (s, 3H), 3.73 (s, 3H), 1.72 (tt, J = 8.3, 4.6 Hz, 1H), 1.32 - 1.24 (m, 2H), 0.97 - 0.88 (m, 2H).547.2161Compound 148 1< H NMR (400 MHz, DMSO-d 6 )δ 9.51 (s, 1H), 9.40 (s, 1H), 8.70 (s, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.52 - 7.45 (m, 2H), 5.80 (s, 2H), 3.86 (s, 3H), 3.72 (s, 3H), 1.77 - 1.66 (m, 1H), 1.10 - 1.02 (m, 2H), 0.89 - 0.80 (m, 2H).563.2162Compound 149 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 5.50 (s, 2H), 4.05 (s, 3H), 3.85 (s, 3H), 3.45 - 3.38 (m, 1H), 1.75 - 1.67 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H), 1.06 - 1.00 (m, 2H), 0.86 - 0.80 (m, 2H).605.4163Compound 156 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.49 (m, 1H), 8.27 (s, 1H), 7.82 - 7.76 (m, 2H), 7.72 (m, 1H), 7.57 - 7.50 (m, 2H), 7.20 (dd, J = 9.3, 6.5 Hz, 1H), 6.94 - 6.86 (m, 1H), 5.54 (s, 2H), 4.06 (s, 3H), 3.86 (s, 3H), 1.79 - 1.68 (m, 1H), 1.08 - 1.00 (m, 2H), 0.90 - 0.81 (m, 2H).596.6164Compound 162 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 8.15 (t,J = 1.4 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.51 (s, 2H), 4.47 - 4.33 (m, 1H), 4.05 (s, 3H), 1.77 - 1.66 (m, 1H), 1.37 (d, J = 6.6 Hz, 6H), 1.08 - 1.00 (m, 2H), 0.88 - 0.79 (m, 2H).592.2165Compound 165 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.67 (s, 1H), 8.25 (s, 1H), 7.60 - 7.44 (m, 4H), 5.49 (s, 2H), 4.04 (s, 3H), 3.86 (s, 3H), 3.66(s, 3H), 1.79-1.70 (m, 2H), 1.06-1.01(m, 4H), 0.87-0.82(m,2H), 0.73-0.70(m,2H).600.6166Compound 166 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.25(s, 1H), 7.93 - 7.91 (m, 2H), 7.46-7.44(m, 2H), 5.50 (s, 2H), 4.04 (s, 3H), 3.85 (s, 3H), 1.71-1.68 (m, 1H), 1.05-1.01(m, 2H), 0.85-0.81(m,2H).563.4 II. Biological Activity Test

[0743] As stated in this application, room temperature refers to a temperature of about 20°C to 30°C.Test Example 1 Experimental Method of USP1 Enzyme Activity 1. Experimental scheme:

[0744] USP1i compounds were screened by USP1 enzyme activity detection experiment.

[0745] 1.1 Experimental materials: recombinant human His6-USP1 / His6-UAF1 composite protein (R&D, catalog number E-568-050); Ubiquitin rhodamine 110 (Ub-Rho) (R&D, catalog number U-555-050); Fluorescent 384-well plate (Perkin Elmer, Art. No. 6007279).

[0746] 1.2 Test sample: Compounds of table 3 in this application, whose structural formulae and preparation methods are shown in the above examples.1.3 Experimental process:

[0747] (1) Preparing 1× detection buffer (improved Tris buffer, comprising 50 mM Tris-HCl (pH 7.8) (Sigma, article number: T2569-1L), 0.01% Tween-20 (Sigma, article number: P2287-100ML), 1 mM DTT (Sigma, article number: D0632-10G), 0.01% BSA (Sigma, article number: B2064-100G) and 0.5 mM EDTA (Invitrogen, article number: 15575020)). (2) Diluting compounds: preparing a 10 mM (mol / L) solution of the compound to be tested with dimethyl sulfoxide (DMSO, with a purity of 100%); diluting the solution of the compound to be detected in a 3-fold gradient to obtain 10 concentrations, wherein the highest concentration is 10 mM; transferring the diluted solution of the compound to be tested to a fluorescent 384-well plate by Echo acoustic liquid handlers, double holes were set for each concentration, and the final concentration of DMSO is 1 vol%; the final concentrations of the solution of the compounds to be tested is 10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1.5 nM and 0.5 nM. (3) Preparing enzyme solution: preparing enzyme solution in 1× detection buffer. (4) Preparing substrate solution: adding Ubiquitin Rhodamine 110 (Ub-Rho) into 1× detection buffer to form the substrate solution. (5) Transferring 10 µL of the enzyme solution prepared in step (3) to the fluorescent 384-well plate. (6) Incubating the resultant for 1 hour at room temperature. (7) Adding 10 µL of the substrate solution prepared in step (4) into each well to start the reaction; wherein the final reaction system composed of 200 nL of the compound to be tested + 10 µL of the enzyme solution + 10 µL of the substrate solution; the final concentration of enzyme is 0.05 nM, and the final concentration of the substrate solution is 300 nM; and the reaction is carried out with centrifuging for 30s and shaking for 30s. (8) Reading the plate on a multifunctional enzyme-labeling instrument SpectraMax Paradigm for 30 minutes, with an excitation wavelength of 480 nm and an emission wavelength of 540 nm. (9) Collecting data regarding SpectraMax Paradigm. (10) Curve fitting: Using Equation (I) to fit data in Excel to obtain the inhibition value; wherein, the maximum signal value represents the luminous signal intensity of the positive control hole without adding the compound of the application; the minimum signal value represents the luminous signal intensity of the negative control hole without enzyme; and the target signal value represents the luminous signal intensity of the Test samples; and fitting the data in XL-Fit with Equation (II) to obtain IC 50 value; Y = Bottom + Top − Bottom / 1 + IC 50 / X × HillSlope wherein Y is the inhibition rate, X is the concentration of the compound; Bottom is the lowest inhibition rate; Top is the highest inhibition rate; and HillSlope is the slope. 2. Experimental results:

[0748] According to the determination, the compounds in the examples of the application have good inhibitory effects on USP1, and the IC 50 values are generally lower than 1000 nanomoles (nM). The IC 50 values of some compounds in the examples of this application are below 100 nM, and more preferably, the IC 50 values of the compounds in the examples of this application are below 50 nM or even below 10 nM. See Table 3 for the results of inhibition of USP1 by some examples of the compounds in this application. Table 3 Enzymatic inhibition results Compound IC 50 (nM)Compound IC 30 (nM)Compound 1 4.04Compound 2 7.55Compound 3 5.55Compound 4 6.85Compound 5 5.63Compound 6 6.07Compound 7 5.81Compound 8 20.96Compound 9 4.07Compound 10 17.85Compound 11 8.91Compound 12 58.26Compound 13-P1 6.01Compound 13-P2 5.00Compound 14 4.32Compound 15 12.24Compound 16 7.55Compound 17 9.28Compound 18 7.38Compound 19 8.25Compound 20 3.26Compound 21 4.39Compound 22 135.00Compound 23 11.67Compound 24 35.53Compound 25 13.41Compound 26 11.49Compound 27 9.95Compound 28 5.95Compound 29 4.62Compound 30 5.71Compound 31 4.85Compound 32 19.07Compound 33 26.07Compound 34 61.98Compound 35 9.82Compound 36 8.98Compound 37 58.01Compound 38 12.09Compound 39 29.94Compound 40 15.05Compound 41 35.20Compound 42 30.44Compound 43 1.29Compound 44 4.22Compound 45 4.40Compound 46 3.60Compound 47 5.26Compound 48 0.92Compound 49 21.17Compound 50 4.84Compound 51 5.90Compound 52 245.29Compound 53 5.58Compound 54 9.88Compound 55 7.90Compound 56 7.65Compound 57 14.75Compound 58 7.90Compound 59 7.21Compound 60 5.34Compound 61 3.14Compound 62 2.65Compound 63 2.74Compound 64 6.12Compound 65 59.57Compound 66 1.62Compound 67 36.07Compound 68 39.19Compound 69 516.62Compound 70 190.71Compound 71 108.13Compound 72 42.90Compound 73 4.90Compound 74 4.13Compound 75 38.53Compound 76 25.26Compound 77 99.09Compound 78 4.39Compound 79 2.04Compound 80 6.55Compound 81 7.15Compound 82 4.45Compound 83 4.62Compound 84 58.96Compound 85 73.51Compound 86 6.96Compound 87 8.56Compound 88 4.50Compound 89 4.70Compound 90 3.65Compound 91 4.16Compound 92 25.95Compound 93 2.56Compound 94 3.69Compound 95 138.33Compound 96 4.89Compound 97 2.10Compound 98 1.26Compound 99 3.13Compound 103 12.35Compound 104 10.15Compound 105 5.17Compound 106 4.56Compound 107 4.65Compound 108 7.52Compound 109 11.86Compound 110 9.50Compound 112 23.90Compound 113 7.73Compound 114 1.89Compound 115 3.03Compound 116 6.48Compound 117 3.54Compound 118 3.57Compound 119 17.77Compound 120 1.97Compound 122 36.00Compound 123 13.72Compound 124 38.53Compound 125 38.00Compound 126 7.10Compound 127 10.15Compound 128 4.80Compound 129 36.00Compound 130 23.90Compound 131 4.68Compound 133 21.99Compound 134 13.00Compound 135 4.40Compound 136 1.34Compound 137 1.54Compound 138 1.80Compound 139 23.51Compound 140 7.29Compound 141 4.00Compound 142 6.20Compound 143 4.67Compound 144 3.17Compound 145 5.91Compound 146 11.60Compound 151 1.00Compound 152 11.00Compound 153 8.50Compound 154 6.20Compound 155 25.97Compound 156 3.50Compound 158 25.66Compound 159 16.55Compound 160 6.20Compound 161 8.13Compound 162 5.49Compound 164 12.00Compound 166 10.22 3. Conclusion:

[0749] It can be seen from the above experimental results that the compounds prepared in the examples of this application have a good inhibitory effect on USP1 and are effective USP1 inhibitors.Test Example 2 USP1 CTG Test Method 1. Experimental scheme

[0750] NCI-H1693 cell killing experiment was used to verify the biological activity of USP1i compound in vitro.1.1 Experimental materials:

[0751] NCI-H1693 cells were purchased from ATCC (article number: CRL-5866) and cultured in a cell incubator with 5% CO 2 (containing 5% CO 2 and 95% air by volume) at 37°C; 1640 complete medium: comprising 94 wt% RPMI-1640 liquid medium (Gibco, article number: 11875-093), 5 wt% FBS (Gibco, article number: 10099-141), and 1 wt% Pen Strep (Gibco, article number: 15070-063); Fluorescent 384-well plate (Perkin Elmer, article number: 6007279); Trypsin (Gibco, article number: 25200056); CTG Buffer (CellTiter-Glo ®< 2.0 Cell Viability Assay, Promega, article number: G9241).1.2 Test sample:

[0752] Compounds of table 4 in this application; wherein the...

Claims

1. A compound represented by formula (II'), or an isomer thereof or a pharmaceutically acceptable salt thereof, wherein, Xa is C or N; ring A is selected from the group consisting of phenyl, 5-6 membered heteroaryl, C5-6 cycloalkyl, and 5-6 membered heterocyclyl; Ra are each independently selected from the group consisting of deuterium, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, oxo, cyano, amino, hydroxy, aminosulfonyl, C1-4 alkylsulfonyl, carbamoyl, C1-4 alkylamino, C3-6 cycloalkyl, C1-4 alkylsulfonylamino, dimethylphosphonoyl, -C1-4 alkyl-OH, -COOC1-4 alkyl, C1-4 alkyl-SO2-NRf-, HO-C1-4 alkyl-SO2-NRf-, 3-6 membered heterocyclyl, -C1-4 haloalkyl-OH, (C1-4 alkyl)2P(O)-, deuterated C1-4 alkyl, and 4-6 membered heterocycloalkyl; wherein C atom(s) in the C1-4 alkyl and C1-4 haloalkyl is / are optionally substituted with N or O; Rf is C3-6 cycloalkyl or C1-4 alkyl; m is 0, 1, 2, 3, or 4; Rb is H or C1-4 alkyl; ring B is selected from the group consisting of phenyl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; Rc are each independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, and deuterated C1-4 alkyl; n is 0, 1, 2, 3, or 4; ring D is selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 9-18 membered fused-heterocyclyl; Re is selected from the group consisting of deuterium, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, ring C, and halogen, wherein ring C is optionally substituted with one Rd; ring C is selected from the group consisting of 5-10 membered heteroaryl comprising 1 to 4 N atom(s) and 8-10 membered fused-heterocyclyl comprising 1 to 4 N atom(s); Rd are each independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, and C3-6 cycloalkyl; 1 is 1, 2, 3, or 4; p is 1, 2, 3, or 4; L1 is selected from the group consisting of C1-4 alkylene, C3-6 cycloalkylene and a chemical bond; when ring A is 5-6 membered heteroaryl, structural unit is not and when ring A is 5-6 membered heterocyclyl, structural unit is not 2. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, having a structure represented by formula (I'): wherein, Xa is C or N; Xb, Xc, and Xd are each independently selected from the group consisting of CH, N, and CR', wherein R' is selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy; ring A is selected from the group consisting of phenyl, 5-6 membered heteroaryl, C5-6 cycloalkyl, and 5-6 membered heterocyclyl; Ra are each independently selected from the group consisting of deuterium, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, oxo, cyano, amino, hydroxy, aminosulfonyl, C1-4 alkylsulfonyl, carbamoyl, C1-4 alkylamino, C3-6 cycloalkyl, C1-4 alkylsulfonylamino, dimethylphosphonoyl, -C1-4 alkyl-OH, -COOC1-4 alkyl, C1-4 alkyl-SO2-NRf-, HO-C1-4 alkyl-SO2-NRf-, 3-6 membered heterocyclyl, -C1-4 haloalkyl-OH, (C1-4 alkyl)2P(O)-, wherein C atom(s) in the C1-4 alkyl and C1-4 haloalkyl is / are optionally substituted with N or O; Rf is C3-6 cycloalkyl or C1-4 alkyl; m is 0, 1, 2, 3, or 4; Rb is H or C1-4 alkyl; ring B is selected from the group consisting of phenyl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; Rc are each independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy; n is 0, 1, 2, 3, or 4; ring C is 5-10 membered heteroaryl comprising 1 to 4 N atom(s); Rd are each independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and deuterated C1-4 alkyl; 1 is 0, 1, 2, 3, or 4; and L1 is selected from the group consisting of C1-4 alkylene, C3-6 cycloalkylene and a chemical bond.

3. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, having a structure represented by formula (I'-1): wherein, Xb, Xc, and Xd are each independently selected from the group consisting of CH, N, and CR', wherein R' is halogen or C1-4 alkoxy; ring A is selected from the group consisting of phenyl, pyridinyl, and C5-6 cycloalkyl; Ra are each independently selected from the group consisting of deuterium, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, oxo, cyano, amino, hydroxy, aminosulfonyl, C1-4 alkylsulfonyl, carbamoyl, C1-4 alkylamino, C3-6 cycloalkyl, C1-4 alkylsulfonylamino, dimethylphosphonoyl, -C1-4 alkyl-OH, -COOC1-4 alkyl, C1-4 alkyl-SO2-NRf-, HO-C1-4 alkyl-SO2-NRf-, 3-6 membered heterocyclyl, -C1-4 haloalkyl-OH, (C1-4 alkyl)2P(O)-, wherein C atom(s) in the C1-4 alkyl and C1-4 haloalkyl is / are optionally substituted with N or O; Rf is C3-6 cycloalkyl or C1-4 alkyl; m is 0, 1, 2, 3, or 4; Rb is H or C1-4 alkyl; ring B is 5-6 membered heteroaryl or 5-10 membered heterocyclyl; Rc are each independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, and halogen; n is 0, 1, 2, 3, or 4; ring C is 5-6 membered heteroaryl comprising 1 to 4 N atom(s); Rd are each independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy; 1 is 0, 1, 2, 3, or 4; and L1 is C1-4 alkylene or C3-6 cycloalkylene.

4. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring D is selected from the group consisting of and 5. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein Re is selected from the group consisting of -CF3, -OCH3, -F, -D, and -CH3.

6. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring A is selected from the group consisting of 7. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Ra is selected from the group consisting of -F, -OCH3, -CF3, -COOCH3, -C(CH3)2-OH, -CHF2, -CN, -Cl, -NH2, CH3-NH-S(O)2-, NH2-S(O)2-, -CH3, -OH, -Br, -CH2CH3, CH(CH3)2, -OCH(CH3)2, D, 8. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein structure unit or structure unit is selected from the group consisting of 9. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein, structure unit or structure unit is selected from the group consisting of and wherein a represents the linking site with ring B, and b represents the linking site with L1.

10. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein, structure unit or structure unit is selected from the group consisting of wherein a represents the linking site with ring B, and b represents the linking site with L1.

11. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein Rb is hydrogen.

12. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein ring B is selected from the group consisting of 13. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein Rc is selected from the group consisting of -OCH3, -CH(CH3)2, -Cl, -OCHF2, -CF3, -CH3, and -OCD3.

14. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein structure unit is selected from the group consisting of and 15. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein ring C is selected from the group consisting of 16. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein Rd is selected from the group consisting of -CF3, -CH3, -CH2CH3, -CH(CH3)2, -OCH2CH3, -CD3, -Cl, -Br, and -F.

17. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein structure unit is selected from the group consisting of 18. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein L1 is selected from the group consisting of -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(C2H5)-, and a chemical bond.

19. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, the compound or the isomer thereof or the pharmaceutically acceptable salt thereof is selected from the group consisting of: and wherein Ra, Rc, Rd, Re, L1, and m are as defined in the preceding claims; and X is selected from the group consisting of C, N, and O.

20. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, the compound or the isomer thereof or the pharmaceutically acceptable salt thereof is selected from the group consisting of: and wherein Ra, Rc, Rd, Re, and m are as defined in the preceding claims; and X is selected from the group consisting of C, N, and O.

21. The compound or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein, the compound or the isomer thereof or the pharmaceutically acceptable salt thereof is selected from the group consisting of:

22. A pharmaceutical composition, comprising a therapeutically effective amount of the compound, or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, and a pharmaceutically acceptable carrier.

23. Use of the compound, or the isomer thereof or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 or the pharmaceutical composition according to claim 22 in the manufacture of a medicament for treating a USP1 target-mediated disease.

24. The use according to claim 23, wherein the USP1 target-mediated disease comprises a cellular inflammatory disease, a neurodegenerative disease, and cancer.

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